Organic compounds as agents for the treatment of aldosterone mediated conditions

ABSTRACT

Compounds of formula I  
                 
provide pharmacological agents which are inhibitors of the P450 enzyme, aldosterone synthase, and thus may be employed for the treatment of aldosterone mediated conditions. Accordingly, the compounds of formula I may be employed for prevention, delay of progression, or treatment of hypokalemia, hypertension, congestive heart failure, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis, and remodeling following hypertension and endothelial dysfunction. Preferred are the compounds of formula I which are selective inhibitors of aldosterone synthase devoid of undesirable side effects due to general inhibition of cytochrome P450 enzymes.

The present invention provides compounds of formula I

wherein

-   -   X is oxygen or H₂ ⁻;    -   Y is —CRR′— in which        -   R and R′ are independently hydrogen, optionally substituted            alkyl, aralkyl or heteroaralkyl;        -   R_(1a) is hydrogen, optionally substituted alkyl,            cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or            heteroaralkyl provided that R_(1a) is not 9H-carbazol-2-yl            when R₂ is methyl, m is zero or an integer of 1, n is zero,            X is H₂, and R_(1b), R₃, R₄ and R₅ are hydrogen;    -   R_(1b) is hydrogen, optionally substituted alkyl, aralkyl,        heteroaralkyl, aryl or heteroaryl; or    -   R_(1a) and R_(1b) combined are alkylene which taken together        with the carbon atom to which they are attached form a 3- to        6-membered ring;    -   R₂ is R₆—(CHR₇)_(p)— in which        -   R₆ is optionally substituted alkyl, cycloalkyl, aryl or            heterocyclyl;        -   R₇ is hydrogen, optionally substituted alkyl, aryl,            heteroaryl or aralkyl;        -   p is zero or an integer from 1 to 4;    -   R₃ and R₄ are is dependently hydrogen, halogen, optionally        substituted alkyl, aryl or heteroaryl; or    -   R₄—C may be replaced by nitrogen;    -   R₅ is hydrogen, optionally substituted alkyl, aryl, heteroaryl,        aralkyl or heteroaralkyl;    -   m and n are independently zero or an integer of 1 provided that        the sum of m and n is not 2;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

The compounds of the present invention are inhibitors of the P450 enzymealdosterone synthase, and, thus, may be employed for the treatment ofaldosterone mediated conditions. Accordingly, the compounds of formula Imay be employed for prevention, delay of progression, or treatment ofhypokalemia, hypertension, congestive heart failure, renal failure, inparticular, chronic renal failure, restenosis, atherosclerosis, syndromeX, obesity, nephropathy, post myocardial infarction, coronary heartdiseases, increased formation of collagen, fibrosis and remodelingfollowing hypertension and endothelial dysfunction. Preferred are thecompounds of formula I which are selective inhibitors of aldosteronesynthase devoid of undesirable side effects due to general inhibition ofcytochrome P450 enzymes.

Listed below are definitions of various terms used to describe thecompounds of the present invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup.

The term “optionally substituted alkyl” refers to unsubstituted orsubstituted straight- or branched-chain hydrocarbon groups having 1-20carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl andthe like. Substituted alkyl groups include, but are not limited to,alkyl groups substituted by one or more of the following groups: halo,hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy,amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy,alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino,heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl,pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.

The term “lower alkyl” refers to those optionally substituted alkylgroups as described above having 1-7, preferably 1-4 carbon atoms.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkenyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon doublebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon triplebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkylene” refers to a straight-chain bridge of 2-5 carbonatoms connected by single bonds, e.g., —(CH₂)_(x)—, wherein x is 2 to 5,which may be interrupted with one or more heteroatoms selected from O,S, S(O), S(O)₂ or NR″, wherein R″ may be hydrogen, alkyl, cycloalkyl,aryl, acyl, carbamoyl, sulfonyl, sulfamoyl, alkoxycarbonyl,aryloxycarbonyl or aralkoxycarbonyl, or the alkylene may be substitutedwith one or more substituents selected from alkyl, cycloalkyl, oxo,halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like.

The term “cycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each ofwhich may be substituted by one or more substituents, such as alkyl,halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino,dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl,sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term “alkoxy” refers to alkyl-O—.

The term “alkanoyl” refers to alkyl-C(O)—.

The term “alkanoyloxy” refers to alkyl-C(O)—O—.

The terms “alkylamino” and “dialkylamino” refer to alkyl-NH— and(alkyl)₂N—, respectively.

The term “alkanoylamino” refers to alkyl-C(O)—NH—.

The term “alkylthio” refers to alkyl-S—.

The term “alkylaminothiocarbonyl” refers to alkyl-NHC(S)—.

The term “trialkylsilyl” refers to (alkyl)₃Si—.

The term “trialkylsilyloxy” refers to (alkyl)₃SiO—.

The term “alkylthiono” refers to alkyl-S(O)—.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.

The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O—.

The term “carboxycarbonyl” refers to HO—C(O)C(O)—.

The term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and thelike.

The term “sulfamoyl” refers to H₂NS(O)₂—, alkyl-NHS(O)₂—,(alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—,heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—, heteroaralkyl-NHS(O)₂— and thelike.

The term “sulfonamido” refers to alkyl-S(O)₂—NH—, aryl-S(O)₂—NH—,aralkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—, heteroaralkyl-S(O)₂—NH—,alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-, aralkyl-S(O)₂—N(alkyl)-,heteroaryl-S(O)₂—N(alkyl)-, heteroaralkyl-S(O)₂—N(alkyl)- and the like.

The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term “optionally substituted amino” refers to a primary or secondaryamino group which may optionally be substituted by a substituent, suchas acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,carbamoyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-12 carbon atoms in the ring portion, such as phenyl,biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionallybe substituted by 1-4 substituents, such as optionally substitutedalkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl,alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio,arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono,sulfonyl, sulfonamido, heterocyclyl and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “aralkanoyl” refers to aralkyl-C(O)—.

The term “aralkylthio” refers to aralkyl-S—.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “arylsulfonyl” refers to aryl-S(O)₂—.

The term “arylthio” refers to aryl-S—.

The term “aroyl” refers to aryl-C(O)—.

The term “aroyloxy” refers to aryl-C(O)—O—.

The term “aroylamino” refers to aryl-C(O)—NH—.

The term “aryloxycarbonyl” refers to aryl-O—C(O)—.

The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl,1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

The term “heterocyclyl” includes substituted heterocyclic groups.Substituted heterocyclic groups refer to heterocyclic groups substitutedwith 1, 2 or 3 substituents selected from the group consisting of thefollowing:

-   -   (a) alkyl;    -   (b) hydroxy (or protected hydroxy);    -   (c) halo;    -   (d) oxo, i.e., ═O;    -   (e) optionally substituted amino, alkylamino or dialkylamino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) carboxy;    -   (i) heterocyclooxy;    -   (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;    -   (k) mercapto;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl or sulfonamido;    -   (o) aryl;    -   (p) alkanoyloxy;    -   (q) aroyloxy;    -   (r) arylthio;    -   (s) aryloxy;    -   (t) alkylthio;    -   (u) formyl;    -   (v) carbamoyl;    -   (w) aralkyl; and    -   (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy,        amino, acylamino, alkylamino, dialkylamino or halo.

The term “heterocyclooxy” denotes a heterocyclic group bonded through anoxygen bridge.

The term “heteroaryl” refers to an aromatic heterocycle, e.g.,monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzofuryl and the like, optionally substituted by,e.g., lower alkyl, lower alkoxy or halo.

The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂—.

The term “heteroaroyl” refers to heteroaryl-C(O)—.

The term “heteroaroylamino” refers to heteroaryl-C(O)NH—.

The term “heteroaralkyl” refers to a heteroaryl group bonded through analkyl group.

The term “heteroaralkanoyl” refers to heteroaralkyl-C(O)—.

The term “heteroaralkanoylamino” refers to heteroaralkyl-C(O)NH—.

The term “acyl” refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl and the like.

The term “acylamino” refers to alkanoylamino, aroylamino,heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

Pharmaceutically acceptable salts of any compound of the presentinvention refer to salts formed with acids, namely acid addition salts,such as of mineral acids, organic carboxylic and organic sulfonic acids,e.g., hydrochloric acid, maleic acid and methanesulfonic acid.

Similarly salts formed with bases, namely cationic salts, such as alkaliand alkaline earth metal salts, such as sodium, lithium, potassium,calcium, magnesium, as well as ammonium salts, such as ammonium,trimethylammonium, diethylammonium, andtris(hydroxymethyl)methylammonium salts and salts with amino acids, arepossible provided an acidic group constitutes part of the structure.

The present invention provides bicyclic compounds, more specifically,bicyclic imidazole and triazole derivatives of formula 1, pharmaceuticalcompositions containing them, methods for preparing said compounds, andmethods of treating aldosterone mediated conditions by administration ofa therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

Preferred are the compounds of formula I wherein

-   -   Y is —CRR′— in which R and R′ are hydrogen;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Further preferred are the compounds of formula I wherein

-   -   m and n are zero;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

More preferred are the compounds of formula IA

wherein

-   -   X is oxygen or H₂;    -   R_(1a) is lower alkyl, aryl or heteroaryl provided that R_(1a)        is not 9H-carbazol-2-yl when R₆ is methyl, p is zero, X is H₂,        and R_(1b), R₃, R₄ and R₅ are hydrogen;    -   R_(1b) is hydrogen, lower alkyl, aralkyl or heteroaralkyl;    -   R₆ is cycloalkyl, aryl or heteroaryl;    -   R₇ is hydrogen or lower alkyl;    -   p is zero or an integer of 1 or 2;    -   R₃, R₄ and R₅ are hydrogen;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Preferred are the compounds of formula IA wherein

-   -   R₁ is monocyclic aryl;    -   R_(1b) is hydrogen, lower alkyl or aralkyl;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Further preferred are the compounds of formula IA of formula IB

wherein

-   -   X is oxygen or H₂;    -   R_(1b) is hydrogen, lower alkyl or aralkyl;    -   R₆ is cycloalkyl, aryl or heteroaryl;    -   R₇ is hydrogen or lower alkyl;    -   p is zero or an integer of 1 or 2;    -   R₈, R₉ and R₁₀ are independently hydrogen, hydroxy, halogen,        cyano, nitro, trifluoromethyl, optionally substituted alkyl,        cycloalkyl, optionally substituted amino, alkoxy, alkylthio,        carboxy, sulfonyl, carbamoyl, aryl, aryloxy, arylthio or        heterocyclyl;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Preferred are the compounds of formula IB wherein

-   -   X is oxygen or H₂;    -   R_(1b) is hydrogen, lower alkyl or aralkyl;    -   R₆ is cycloalkyl, aryl or heteroaryl;    -   R₇ is hydrogen or lower alkyl;    -   p is an integer of 1;    -   R₈ is hydrogen;    -   R₉ is hydrogen, halogen, cyano or trifluoromethyl;    -   R₁₀ is halogen, cyano or trifluoromethyl;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Further preferred are the compounds of formula IB wherein

-   -   X is oxygen;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Further preferred are also the compounds of formula IB wherein

-   -   R₆ is C₃₋₆cycloalkyl, monocyclic aryl or monocyclic heteroaryl;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Further preferred are also the compounds of formula IB wherein

-   -   R₁₀ is located at the 3-position;        or a pharmaceutically acceptable salt thereof; or a diastereomer        thereof; or a mixture of diastereomers thereof; or an optical        isomer thereof; or a mixture of optical isomers thereof.

Particular embodiments of the invention are:

-   4-(7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Allyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(6-Oxo-7-propyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Isopropyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-{7-[2-(4-Fluoro-phenyl)-ethyl]-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl}-benzonitrile;-   4-[7-(3-Morpholin-4-yl-propyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   7-(4-Methoxy-benzyl)-5-(4-thiophen-3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   4-[7-(4-Methyl-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-[7-(4-Chloro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   4-[6-Oxo-7-(4-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzo    nitrile;-   4-[6-Oxo-7-(3-methyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-[6-Oxo-7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-[6-Oxo-7-(3-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-[6-Oxo-7-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Cyclopropyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Cyclohexyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(7-Cyclopentyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-[7-(2-Methoxyethyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   4-[7-(3-Methoxypropyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   4-(6-Oxo-7-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   7-Benzyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-Methyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-cyclopropylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-Benzyl-5-(4-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-chloro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-methoxy-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-fluoro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-cyclohexyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-methoxy-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-cyclopropylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-Benzyl-5-(3-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-chloro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(3-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(3-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(3-methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-methoxy-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-chloro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(3-chloro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-methyl-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-(4-fluoro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-thiophen-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-furan-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-thiophen-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-furan-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-pyridin-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-pyridin-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-pyridin-4-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-cyclohexylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   4-[5-(3-Bromo-phenyl)-6-oxo-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-ylmethyl]-piperidine-1-carboxylic    acid t-butyl ester;-   5-(3-Bromo-phenyl)-7-piperidin-4-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (R)-5-(3-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (S)-5-(3-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (R)-5-(3-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (S-5-(3-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (R)-5-(4-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (S)-5(4-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (R)-5-(4-Bromo-phenyl)-7-((3)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   (S)-5-(4-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   4-[(R)-6-Oxo-7-((S)-1-phenyl-ethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   4-[(S-6-Oxo-7-((S)-1-phenyl-ethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   7-Benzyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-(4-Methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-(4-Fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   3-(7-Benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   3-[7-(4-Methyl-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   3-[7-(4-Fluoro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   3-[7-(4-Chloro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   3-[7-(4-Methoxy-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   3-[7-(4-Fluoro-phenethyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   3-(7-Phenethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   3-(7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   5-(4′-Chloro-biphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-(4-Methoxy-benzyl)-5-(4-thiophen-3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-Cyclopropylmethyl-5-(4-thiophen-3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-Benzyl-5-(4′-fluoro-biphenyl-3-yl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-Biphenyl-4-yl-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   7-Benzyl-5-biphenyl-3-yl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   Methyl    4-(7-benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzoate;-   4-(7-Benzyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   5-(4-Bromo-phenyl)-7-cyclopropylmethyl-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(3-Bromo-phenyl)-7-cyclopropylmethyl-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   5-(4-Bromo-phenyl)-7-(4-fluoro-benzyl)-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   4-[7-(4-Fluoro-benzyl)-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   4-[((R)-7-[(S)-1-(4-Fluoro-phenyl)-ethyl]-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;-   4-{(S)-7-[(S)-1-(4-Fluoro-phenyl)-ethyl]-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl}-benzonitrile;-   5-Benzyl-5-(4-bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;-   4-(5,7-Dibenzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   4-(5-Benzyl-7-cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;-   5(4-Bromophenyl)-7-(4-methoxy-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]-pyrazine;-   4-(8-Benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile;    and-   4-(8-Cyclopropylmethyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile;    or a pharmaceutically acceptable salt thereof; or an optical isomer    thereof; or a mixture of optical isomers thereof.

The compounds of the invention depending on the nature of thesubstituents, may possess one or more asymmetric centers. The resultingdiastereoisomers, enantiomers and geometric isomers, and mixturesthereof, are encompassed by the instant invention.

Compounds of formula I may be prepared starting from alcohols of formulaII

wherein Y and n have meanings as defined herein above, and R′₃, R′₄ andR′₅ represent R₃, R₄ and R₅ as defined herein above, or R′₃, R′₄ and R′₅are groups convertible to R₃, R₄ and R₅, respectively. Alcohols offormula II may be prepared as illustrated herein in the Examples, ormodifications thereof, or using methods well-known in the art.

Accordingly, compounds of formula II may first be treated with compoundsof formula IIIPg₁-Lg₁  (III)wherein Lg₁ represents a leaving group, such as iodide, bromide orchloride, preferably chloride, and Pg₁ is an appropriate N-protectinggroup, such as trityl, benzyloxymethyl, methoxymethyl or(2-trimethylsilylethoxy)methyl, preferably trityl, in the presence of abase, such as triethylamine (TEA), diisopropylethylamine (DIEA) orN-methylmorpholine (NMM) in an organic solvent, such as tetrahydrofuran(THF) or N,N-dimethylformamide (DMF) at an ambient temperature,preferably at room temperature (RT), to afford compounds of formula IV

wherein Pg₁, Y, n, R′₃, R′₄ and R′₅ have meanings as defined for formulaII.

Compounds of formula IV wherein Pg₁, Y, n, R′₃, R′₄ and R′₅ havemeanings as defined herein above, may be converted to compounds offormula V

wherein Pg₂ is an appropriate O-protecting group, such as atrialkylsilyl or an acyl group, preferably a t-butyidimethylsilyl or anacetyl group, and Pg₁, Y, n, R′₃, R′₄ and R′₅ have meanings as definedherein above, using methods described herein in the Examples, ormodifications thereof, or using conditions well-known in the art. Forexample, compounds of formula IV may be treated at RT with a compound offormula VIPg₂-Lg₂  (VI)wherein Lg₂ represents a leaving group, such as iodide, bromide,chloride or trifluoromethanesulfonate, and Pg₂ is an O-protecting groupsuch as trialkylsilyl, e.g., t-butyidimethylsilyl, in an organicsolvent, such as THF, DMF or dichloromethane (DCM) in the presence of abase such as TEA, DIEA, NMM, imidazole or N,N-dimethylaminopyridine(DMAP), to afford compounds of formula V, wherein Pg₁, Pg₂, Y, n, R′₃,R′₄ and R′₅ have meanings as defined herein above.

Alternatively, compounds of formula IV may be converted to compounds offormula V, wherein Pg₂ is an O-protecting group, such as an acyl group,e.g., acetyl, by the treatment with acyl anhydride or acyl chloride,e.g., acetic anhydride or acetyl chloride, in the presence of a base,such as pyridine.

Compounds of formula V, wherein Pg₁, Pg₂, Y, n, R′₃, R′₄ and R′₅ havemeanings as defined herein above may be first treated at an ambienttemperature, preferably at RT, with an alkylating agent of formula VII

wherein m is zero, Lg₃ represents a leaving group, such as bromide,chloride, methanesulfonate or p-toluenesulfonate, preferably bromide,R₁₁ is lower alkyl, such as methyl or ethyl, Y has a meaning as definedherein above, R′_(1b) is hydrogen, and R′_(1a) represents R_(1a) asdefined herein, or R′_(1a) is a group convertible to R_(1a), in anorganic solvent, such as ethyl acetate (EtOAc) or acetonitrile.Subsequent removal of the protecting groups Pg₁ and Pg₂ then affordscompounds of formula VIII

wherein m is zero, R′_(1b) is hydrogen, and R₁₁, Y, n, R′_(1a), R′₃, R′₄and R′₅ have meanings as defined herein above. The protecting groups maybe removed using conditions illustrated herein in the Examples, ormodifications thereof, or using methods well-known in the art. Inparticular, when Pg₁ is a trityl and Pg₂ is a t-butyidimethylsilylgroup, both protecting groups may be removed simultaneously by thetreatment with an acid, such as trifluoroacetic acid, p-toluenesulfonicacid or a mineral acid, preferably hydrochloric acid, in the presence ofa protic organic solvent, such as a lower alcohol, preferably methanolor ethanol. Protecting groups (Pg₂), such as an acyl group, inparticular, acetyl group, may be removed by the subsequent treatmentwith an aqueous base, such as sodium, lithium or potassium hydroxide inan organic solvent, such as THF or a lower alcohol, preferably THF.Alkylating agents of formula VII may be prepared using methods describedherein in the Examples, or modifications thereof, or using conditionswell-known in the art.

Alternatively, compounds of formula VIII wherein m is zero or an integerof 1, R₁₁, Y, n, R′_(1a), R′₃, R′₄ and R′₅ have meanings as definedherein above, and R′_(1b) represents hydrogen, optionally substitutedalkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, may be obtained byfirst treating compounds of formula V at an ambient temperature,preferably at a temperature near the boiling point of the solvent, withan alkylating agent of formula IX

wherein Lg₄ represents a leaving group, such as bromide, chloride,methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate,preferably bromide, and R′_(1a) and R′_(1b) represent R_(1a) and R_(1b)as defined herein, or R′_(1a) and R′_(1b) are groups convertible toR_(1a) and R_(1b), respectively, in an organic solvent such as EtOAc oracetonitrile. Subsequent removal of the protecting groups Pg₁ and Pg₂using conditions described herein above for the preparation of compoundsof formula VIII then affords compounds of formula X

wherein Y, n, R′_(1a), R′_(1b), R′₃, R′₄ and R′₅ have meanings asdefined herein above.

The free hydroxyl group in compounds of formula X, wherein Y, n,R′_(1a), R′_(1b), R′₃, R′₄ and R′₅ have meanings as defined hereinabove, may then be protected with an appropriate O-protecting group,such as trialkylsilyl, preferably t-butyldimethylsilyl, using conditionsas described herein above for the preparation of compounds of formula V,to obtain compounds of formula XI

wherein Pg₃ represents the above defined O-protecting group, and Y, n,R′_(1a), R′_(1b), R′₃, R′₄ and R′₅ have meanings as defined hereinabove.

Compounds of formula XI, wherein Pg₃, Y, n, R′_(1a), R′_(1b), R′₃, R′₄and R′₅ have meanings as defined herein above, may then be converted tocompounds of formula XII

wherein R₁₁, Pg₃, Y, m, n, R′_(1a), R′_(1b), R′₃, R′₄ and R′₅ havemeanings as defined herein above, by first deprotonating compounds offormula XI in the presence of a base, such as lithium diisopropylamide(LDA), or lithium, sodium or potassium bis(trimethylsilyl)amide,preferably lithium bis(trimethylsilyl)amide (LHMDS), in an organicsolvent, such as THF at a temperature ranging from −45° C. to −100° C.The resulting anion may then be reacted with an acylating agent or analkylating agent of formula XIIILg₅-(Y)_(m)—C(O)—OR₁₁  (XIII)wherein m is zero (an acylating agent) or an integer of 1 (an alkylatingagent), Lg₅ is a leaving group, such as chloride or cyanide when m iszero, or Lg₅ is a leaving group, such as bromide or chloride when m isan integer of 1, and R₁₁ has a meaning as defined herein above, toafford compounds of formula XII.

Compounds of formula VIII, wherein R₁₁, Y, m, n, R′_(1a), R′_(1b), R′₃,R′₄ and R′₅ have meanings as defined herein above may then be obtainedfrom compounds of formula XII by removal of the protecting group, Pg₃,using conditions described herein above or modifications thereof.

Compounds of formula VIII, wherein R₁₁, Y, m, n, R′_(1a), R′_(1b), R′₃,R′₄ and R′₅ have meanings as defined herein above, may be oxidized tocompounds of formula XIV

wherein R₁₁, Y, m, n, R′^(1a), R′_(1b), R′₃, R′₄ and R′₅ have meaningsas defined herein above, using an oxidizing agent, preferablyDess-Martin reagent, in an organic solvent, such as DCM or1,2-dichloromethane (DCE).

Finally, compounds of formula XIV, wherein R₁₁, Y, m, n, R′_(1a),R′_(1b), R′₃, R′₄ and R′₅ have meanings as defined herein above may becyclized at an ambient temperature ranging from RT to the boiling pointof the solvent to afford compounds of formula I′

wherein X represents oxygen, and R₂, Y, m, n, R′_(1a), R′_(1b), R′₃, R′₄and R′₅ have meanings as defined herein above, under conditions ofreductive amination, e.g., compounds of formula XIV may be treated withamines of formula XVR₂—NH₂  (XV)or acid addition salts thereof, wherein R₂ has a meaning as definedherein above, in the presence of a reducing agent, such as sodium orlithium borohydride, sodium cyanoborohydride or sodiumtriacetoxyborohydride, preferably sodium triacetoxyborohydride, in anorganic solvent, such as THF, DCM or DCE to afford compounds of formulaI′, wherein X, R₂, Y, m, n, R′_(1a), R′_(1b), R′₃, R′₄ and R′₅ havemeanings as defined herein above. The cyclization may be carried out inthe presence of an acid catalyst, such as acetic or trifluoroaceticacid.

Compounds of formula I′, wherein X represents oxygen; R′_(1b) ishydrogen and R₂, Y, m, n, R′_(1a), R′₃, R′₄ and R′₅ have meanings asdefined herein above, may be converted to compounds of formula I′,wherein R′_(1b) is optionally substituted alkyl, aralkyl orheteroaralkyl, by treatment with an alkylating agent of formula XVIR′_(1b)-Lg₆  (XVI)wherein R′_(1b) is optionally substituted alkyl, aralkyl orheteroaralkyl, and Lg₆ represents a leaving group, such as bromide,chloride, methanesulfonate, p-toluenesulfonate ortrifluoromethanesulfonate, preferably bromide, in the presence of abase, such as sodium hydride, LDA or LHMDS, in an organic solvent, suchas THF or DMF.

Similarly, compounds of formula I′, wherein X represents oxygen, R′_(1a)and R′_(1b) are hydrogen, and R₂, Y, m, n, R′₃, R′₄ and R′₅ havemeanings as defined herein above, may be converted to compounds offormula I′, wherein R′_(1a) and R′_(1b) combined are alkylene, bytreatment with an alkylating agent of formula XVIILg₇-R′_(1a)—R′_(1b)-Lg₇  (XVII)wherein R′_(1a) and R′_(1b) combined are alkylene, and Lg₇ represents aleaving group, such as bromide or chloride, preferably bromide, in thepresence of a base, such as sodium hydride, potassium carbonate orcesium carbonate, in an organic solvent, such as dimethylsulfoxide orDMF.

In addition, compounds of formula I′, wherein X represents oxygen, andR₂, Y, m, n, R′_(1a), R′_(1b), R′₃, R₁₄ and R′₅ have meanings as definedherein above, may be reduced to compounds of formula I′, wherein Xrepresents H₂, by treatment with a reducing agent, preferably borane, inan inert solvent, such as THF.

The processes described herein above may be conducted under inertatmosphere, preferably under nitrogen atmosphere.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxyl groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxyl groups without themolecular framework being destroyed or other undesired side reactionstaking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably ator near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

The invention also relates to any novel starting materials,intermediates and processes for their manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, diastereomers, optical isomers (antipodes), racemates ormixtures thereof. The aforesaid possible isomers or mixtures thereof arewithin the purview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, the imidazolyl and triazolylmoieties may be employed to resolve the compounds of the presentinvention into their optical antipodes, e.g., by fractionalcrystallization of a salt formed with an optically active acid, e.g.,tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid,di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid orcamphor-10-sulfonic acid. Racemic products can also be resolved bychiral chromatography, e.g., high pressure liquid chromatography (HPLC)using a chiral adsorbent.

Finally, compounds of the invention are either obtained in the freeform, as a salt thereof, or as prodrug derivatives thereof.

Compounds of the invention having basic groups, in particular, theimidazolyl or triazolyl moiety, can be converted into acid additionsalts, especially pharmaceutically acceptable salts. These are formed,for example, with inorganic acids, such as mineral acids, for example,sulfuric acid, a phosphoric or hydrohalic acid, or with organiccarboxylic acids, such as (C₁-C₄)-alkanecarboxylic acids which, forexample, are unsubstituted or substituted by halogen, for example,acetic acid, such as saturated or unsaturated dicarboxylic acids, forexample, oxalic, succinic, maleic or fumaric acid, such ashydroxycarboxylic acids, for example glycolic, lactic, malic, tartaricor citric acid, such as amino acids, for example, aspartic or glutamicacid, or with organic sulfonic acids, such as (C₁-C₄)-alkylsulfonicacids, for example, methanesulfonic acid; or arylsulfonic acids whichare unsubstituted or substituted (for example by halogen). Preferred aresalts formed with hydrochloric acid, methanesulfonic acid and maleicacid.

Compounds of the instant invention which contain acidic groups may beconverted into salts with pharmaceutically acceptable bases. Such saltsinclude alkali metal salts, like sodium, lithium and potassium salts;alkaline earth metal salts, like calcium and magnesium salts; ammoniumsalts with organic bases, e.g., trimethylamine salts, diethylaminesalts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

Prodrug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Exemplary prodrugderivatives are, e.g., esters of free carboxylic acids and S-acyl andO-acyl derivatives of thiols, alcohols or phenols, wherein acyl has ameaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art.

In view of the close relationship between the free compounds, theprodrug derivatives and the compounds in the form of their salts,whenever a compound is referred to in this context, a prodrug derivativeand a corresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, to inhibit aldosteronesynthase, and for the treatment of conditions associated withaldosterone synthase activity. Such conditions include hypokalemia,hypertension, congestive heart failure, renal failure, in particularchronic renal failure, restenosis, atherosclerosis, syndrome X, obesity,nephropathy, post-myocardial infarction, coronary heart diseases,increased formation of collagen, fibrosis, and remodeling followinghypertension and endothelial dysfunction. The said pharmaceuticalcompositions comprise a therapeutically effective amount of apharmacologically active compound of the instant invention, alone or incombination with one or more pharmaceutically acceptable carriers.

Thus in an additional aspect the present invention concerns apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention in combination with one or morepharmaceutically acceptable carriers.

In a further aspect the present invention concerns a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention in combination with a therapeutically effective amountof anti-obesity agent, anti-hypertensive agent, inotropic agent orhypolipidemic agent.

A pharmaceutical composition as described above for use as a medicament.

Use of a pharmaceutical composition or combination as described abovefor the preparation of a medicament for the treatment of conditionsassociated with aldosterone synthase activity.

A pharmaceutical composition as described above for the treatment ofconditions associated with aldosterone synthase activity, preferablyhypokalemia, hypertension, congestive heart failure, atherosclerosis,coronary heart diseases, post myocardial infarction, restenosis,increased formation of collagen, fibrosis, remodeling followinghypertension and endothelial dysfunction, renal failure, nephropathy,syndrome X and obesity.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising atherapeutically effective amount thereof in conjunction or admixturewith excipients or carriers suitable for either enteral or parenteralapplication. Preferred are tablets and gelatin capsules comprising theactive ingredient together with:

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g. starches, agar, alginic acid or Its        sodium salt, or effervescent mixtures; and/or    -   e) absorbants, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpre-determined rate over a prolonged period of time, and means to securethe device to the skin.

The pharmaceutical formulations contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include anti-obesity agents, such as orlistat, anti-hypertensiveagents, inotropic agents and hypolipidemic agents, e.g., loop diuretics,such as ethacrynic acid, furosemide and torsemide; angiotensinconverting enzyme (ACE) inhibitors, such as benazepril, captopril,enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril,ramipril and trandolapril; inhibitors of the Na—K-ATPase membrane pump,such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEPinhibitors, such as omapatrilat, sampatrilat and fasidotril; angiotensinII antagonists, such as candesartan, eprosartan, irbesartan, losartan,telmisartan and valsartan, in particular valsartan; O-adrenergicreceptor blockers, such as acebutolol, atenolol, betaxolol, bisoprolol,metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents,such as digoxin, dobutamine and milrinone; calcium channel blockers,such as amlodipine, bepridil, diltiazem, felodipine, nicardipine,nimodipine, nifedipine, nisoldipine and verapamil; and3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA) inhibitors,such as lovastatin, pitavastatin, simvastatin, pravastatin,cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin,atorvastatin, rosuvastatin and rivastatin. A compound of the presentinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

A unit dosage for a mammal of about 50-70 kg may contain between about 1and 1000 mg, advantageously between about 5-500 mg of the activeingredient. The therapeutically effective dosage of a compound offormula I is dependent on the species of warm-blooded animal (mammal),the body weight, age and individual condition, on the form ofadministration and on the compound involved.

The compounds of the present invention are inhibitors of aldosteronesynthase, and thus may be employed for the treatment of conditionsassociated with aldosterone synthase activity, as described herein,e.g., hypokalemia, hypertension, congestive heart failure, renalfailure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction.

Thus, in an additional embodiment, the present invention relates to;

A compound of the invention for use as a medicament.

The use of a compound of the invention for the preparation of apharmaceutical composition for the prevention and/or treatment ofconditions associated with aldosterone synthase activity.

A method for the prevention and/or treatment of conditions associatedwith aldosterone synthase activity, which comprises administering atherapeutically effective amount of a compound of the invention.

In accordance with the foregoing the present invention provides in a yetfurther aspect:

A therapeutic combination, e.g. a kit, kit of parts e.g. for use in anymethod as defined herein, comprising a compound of formula I, in freeform or in pharmaceutically acceptable salt form, to be usedconcomitantly or in sequence with at least one pharmaceuticalcomposition comprising an anti-obesity agent, anti-hypertensive agent,inotropic agent or hypolipidemic agent. The kit may compriseinstructions for its administration.

A kit of parts comprising

(i) a pharmaceutical composition of the invention, (ii) a pharmaceuticalcomposition comprising a compound selected from an anti-obesity agent,anti-hypertensive agent, inotropic agent or hypolipidemic agent, or apharmaceutically acceptable salt thereof, in the form of two separateunits of the components (i) to (ii).

A method as defined above comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective amount of acompound of formula I in free form or in pharmaceutically acceptablesalt form, and a second drug substance, said second drug substance beingan anti-obesity agent, anti-hypertensive agent, inotropic agent orhypolipidemic agent, e.g. as indicated above.

Preferably the compound of the invention is administered to a mammal inneed thereof.

Preferably the compound of the invention is used for the treatment of adisease which responds to an inhibition of aldosterone synthase.

Preferably the conditions associated with aldosterone synthase activityare selected from hypokalemia, hypertension, congestive heart failure,renal failure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction.

A method or use according to the invention which comprises administeringsaid compound in combination with a therapeutically effective amount ofanti-obesity agent, anti-hypertensive agent, inotropic agent orhypolipidemic agent.

A method or use according to the invention which comprises administeringsaid compound in the form of a pharmaceutical composition as describedherein.

As used throughout the specification and in the claims, the term“treatment” embraces all the different forms or modes of treatment asknown to those of the pertinent art and in particular includespreventive, curative, delay of progression and palliative treatment.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. Said compounds can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo either enterally, parenterally, advantageouslyintravenously, e.g., as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻³ molar and 10⁻⁹ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 0.1 and 500mg/kg, preferably between about 1 and 100 mg/kg.

The activity of a compound according to the invention can be assessed bythe following methods or methods well-described in the art:

The aldosterone synthase inhibitory activity in vitro may be determinedas follows:

Adult male Sprague-Dawley rats weighing 125-150 g are obtained fromHarlan Farms. All animals are caged in pairs and maintained understandard conditions of light and temperature. The animals are placed ona sodium depleted diet (0.01-0.02%) from Harland Teklad, Madison Wis.(cat# TD90228) and maintained on normal drinking water ad libitum. Theanimals are maintained on this diet for two to four weeks prior toharvesting the adrenal glomerulosa cells. The rats are killed by CO₂inhalation, and the adrenals are immediately removed and placed in thesame ice-cold buffer used during homogenization and assay of the enzymepreparation. The adrenals are decapsulated to obtain the glomerulosatissue. The tissue is homogenized in a glass homogenizer containing Trisassay buffer (8.5 mM MgCl₂, 2.7 mM CaCl₂, 3.13 mM KCl, 7.59 mM NaCl,0.1% TEA and 50 mM Tris HCl adjusted to pH 7.4). The homogenate isdiluted so that 37.5 mg of glomerulosa tissue is in each mL of buffer.The homogenate is centrifuged at 4° C. at 900×g for 10 min. To start theassay, and 200 μL aliquots (450-550 μg of protein) of the adrenalcytoplasmic preparation is added to each glass tube containing 2.5×10⁻⁴M NADPH, 4×10⁻⁶ M corticosterone. The final corticosterone concentrationconsisted of 4×10⁻⁶ M corticosterone (C-2505, Sigma Chemical Co, St.Louis, Mo.) and 1×10⁻⁸ M [1,2,6,7-³H] corticosterone (70 Ci/mM; NET 399;NEN™ Life Sciences Product, Inc., Boston, Mass.) and variousconcentrations of the putative aldosterone synthase inhibitor asindicated. The final volume of the incubation mixture is 0.5 mL. Themixture is incubated for 1 h at 25° C. in a Dubnoff shaking incubator at1 atm of 95% O₂/5% CO₂. The reaction is stopped by the addition of 7 mLEtOAc, and the steroids extracted after vortexing. The water phase isextracted again with 3 mL of EtOAc. The combined extracts are driedunder nitrogen, reconstituted in EtOAc, and spotted on silica gel TLCplates (LK6F; cat. # 4866-820; Whatman, Inc. Clifton, N.J.). Thechromatograms are developed in a solvent system of toluene:acetone:water(120:80:0.8 v/v) for 60 min. The plates are scanned for radioactivitywith a Bioscan System 200 Imaging Scanner (Bioscan, Ish. DC). The twoproducts of the aldosterone synthase, 18-OH-corticosterone andaldosterone are scraped and counted in a liquid scintillation counter(Beckman LS6000TA, Beckman Instr., Palo Alto, Calif.).

The IC₅₀s are determined from a logit-log plot (pseudo-Hill plot)according to the equation (see Pratt and Taylor, Eds, “Principles ofDrug Action”, Churchill Livingstone Inc, NY (1990)):log P/(100−P)=n log[I]+n log IC ₅₀where P is the percent competition of specific binding in the presenceof a given concentration of inhibitor (I). The slope (Hill Coefficient)and x intercept (IC₅₀) are determined by linear regression of theexperimental data. The Km(app) is calculated by a computer programaccording to the Hanes equation (see Cornish-Bowden, Ed., “Principles ofEnzyme Kinetics”, Butterworth & Co., Boston, Mass. (1976)):s/v=Km/V+s/Vwhere Km=Michaelis constant, V=maximum velocity, s=substrateconcentration, v=velocity.

The aromatase inhibitory activity in vitro may be determined as follows:

Human placental microsome fraction is prepared from freshly deliveredhuman term placenta as previously described with minor modifications(see Steele et al., Steroids, Vol. 50, pp. 147-161 (1987)). The tissueis freed of membranes and large vessels and rinsed repeatedly with 0.15M KCl (4° C.). It is then minced in 0.25 M sucrose and homogenized. Thehomogenate is centrifuged at 20,000×g for 30 min. The supernatant isthen centrifuged at 148,000×g for 60 min. The microsomal pellet obtainedis re-suspended in 0.05 M potassium phosphate buffer pH 7.4 andcentrifuged again at 148,000×g for 60 min. The resulting pellet isre-suspended in phosphate buffer, divided into aliquots, and stored at−40° C.

Human placental aromatase assay is performed in a incubation mixtureconsisting of: 12.5 mM phosphate buffer (12.5 mM KH₂PO₄, 1 mM EDTA, 1.6mM dithiothreitol and 1.0 g/L of albumin; pH 7.5), NADPH (2.4×10⁻⁴ M),1β-³H androstenedione (1×10⁻⁷ M) and the appropriate concentration ofthe desired inhibitor. The assay is started by pipetting the appropriateamount 50-500 μg of the human placental microsome preparation into theincubation mixture. The mixture is incubated at 37° C. for 20 min andstopped by addition of 6 volumes of chloroform. The samples areimmediately vortexed and centrifuged. The aqueous layer is carefullyremoved so as to avoid contamination with chloroform. The aqueousfraction is treated with an equal volume of a 5% aqueous suspension ofcharcoal to remove any substrate not extracted by the chloroform. Aftercentrifugation an aliquot of the aqueous phase is counted in a liquidscintillation counter. The enzymatic activity for each concentration ofinhibitor is calculated as a percent of the vehicle control, which isarbitrarily set at 100%. Therefore, the relative enzyme inhibition isexpressed as a percentage: 100% minus % enzyme activity with inhibitorpresent.

The aldosterone synthase inhibitory activity for reduction of cardiacdamage in vivo may be evaluated as follows:

The protocol is nearly identical to that previously described (see Rochaet al., Endocinology, Vol. 141, pp. 3871-3878 (2000)) with minormodifications. The rats are housed in individual cages and given 0.9%NaCl as drinking fluid ad libitum throughout the experiment. Three dayslater rats are placed on one of the three dosing protocols. Group 1(control) receives L-NAME for 14 days, and on day 11 of L-NAMEtreatment, an osmotic mini-pump containing only saline is implanted ineach animal subcutaneously (s.c.). Group 2 (/L-NAME/Ang II) receivedL-NAME for 14 days, and on day 11 of L-NAME treatment, an osmoticmini-pump containing Ang II is implanted in each animal s.c. Group 3(L-NAME/Ang II/test compound) is treated similarly to Group 2 butreceives test compound (4 mg/kg/day) orally once a day. The testcompound is dissolved in distilled water and given by gavage; whereasGroups 1 and 2 receive the vehicle. The experiment is concluded on day14 of L-NAME treatment. The L-NAME (Sigma Chemical Co., St. Louis, Mo.)is administered in the 0.9% NaCl drinking water at a concentration of 60mg/100 mL which results in a daily intake of approximately 60 mg/kg. AngII is administered via Alzet osmotic mini-pumps (Model 2001; Alza Corp,Palo Alto, Calif.). The mini-pump is implanted s.c. at the nape of theneck. Ang II (human, 99% peptide purity) is purchased from SigmaChemical Co., St. Louis, Mo. and administered at a dose of 225 μg/kg/dayin saline. The concentration of Ang II used to fill the pumps iscalculated based upon: (a) the mean pump rate provided by themanufacturer; (b) the body weight of the animals on the day beforeimplantation of the pumps; and (c) dose planned. The rats are sacrificedon day 14. Their hearts are removed and sliced through theventricle/atrium in a “bread-loaf” manner, yielding three samples fromthe following gross cardiac regions: superior, middle and inferior. Thesamples are fixed in 10% buffered formalin. Paraffin sections are cutand stained with hematoxylin/eosin. A single investigator who is blindedto the experimental groups views slides. One slide from each of threegross cardiac sample regions is analyzed per rat. Cardiac sites (leftand right ventricles and the septum) are evaluated separately. Theentire section is assessed histologically for the presence of myocardialdamage (regardless of the severity) as evidenced by the presence ofmyocyte necrosis, inflammatory cells, hemorrhage and general tissuedisruption. Evaluation of the histological data is made by comparingGroups 2 and 3, i.e., ANG II with or without test compound.

Illustrative of the invention, the compounds of Examples 1, 3 and 32inhibit the aldosterone synthase activity with an IC₅₀ value of about 12nM, 4 nM and 9 nM, respectively.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure,preferably between about 10 and 100 mmHg (=20-133 mbar). The structureof final products, intermediates and starting materials is confirmed bystandard analytical methods, e.g., microanalysis, melting point (m.p.)and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations usedare those conventional in the art. The concentration for [α]_(D)determinations is expressed in mg/mL.

EXAMPLE 14-(7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

A. 1-Trityl-4-hydroxymethyl-1H-imidazole

To a stirred solution of 4(5)-hydroxymethylimidazole (15.7 g, 117 mmol)in DMF (200 mL) is added TEA (40.0 mL, 287 mmol) followed by tritylchloride (34.3 g, 123 mmol). The reaction mixture is stirred at RT for 8h before it is poured into water. The collected solid is washedsuccessively with water and diethyl ether and dried under reducedpressure. The solid is then re-crystallized from 1,4-dioxane to yield1-trityl-4-hydroxymethyl-1H-imidazole: m.p. 228-230° C.; ¹H-NMR(DMSO-d₆) δ 7.37 (9H, m), 7.35 (1H, s), 7.09 (6H, m), 6.78 (1H, s), 4.90(1H, br s), 4.34 (2H, s); e/z (ES) 341 (M+1, 5%), 243 (100%).

B. 4-Acetoxymethyl-1-trityl-1H-imidazole

To a suspension of the title A compound1-trityl-4-hydroxymethyl-1H-imidazole (34.5 g, 101 mmol) in pyridine(200 mL) is added acetic anhydride (28.6 mL, 303 mmol) in a dropwisefashion and the reaction is stirred until it becomes clear. The reactionmixture is poured into EtOAc and then washed with 0.5N aqueous HCl,saturated aqueous sodium bicarbonate and brine. The combined organicphases are dried over anhydrous sodium sulfate and then filtered througha silica pad yielding a solid after removal of the solvent in vacuo. Thesolid is triturated with diethyl ether to give4-acetoxymethyl-1-tritylimidazole: m.p. 133-134° C.; ¹H-NMR (DMSO-d₆) δ7.42 (10H, m), 7.09 (6H, m), 6.99 (1H, s), 4.89 (2H, s), 1.99 (3H, s);e/z (ES) 383 (M+1, 5%), 243 (100%).

C. 4-(5-Acetoxymethyl-imidazoyl-1-ylmethyl)-benzonitrile hydrobromide

The title B compound 4-acetoxymethyl-1-tritylimidazole (35.4 g, 92.7mmol) and 4-cyanobenzylbromide (18.3 g, 93.3 mmol) are combined in EtOAcand heated at reflux for 16 h, the precipitated solid is filtered off,and washed thoroughly with EtOAc. The combined filtrate is eveporated to30 mL and heated at reflux for 1 h and the precipitate again filteredoff and washed with EtOAc. This is repeated by heating the EtOAc (10 mL)for 1 h and filtering. The combined solids are dissolved in methanol andheated at reflux for 1 h before evaporating the solvent in vacuo. Theresidue is triturated with diethyl ether to yield4-(5-acetoxymethyl-imidazoyl-1-ylmethyl)-benzonitrile hydrobromide:¹H-NMR (DMSO-dB) δ 9.38 (1H, s), 7.92 (2H, d, J=8.4), 7.90 (1H, s), 7.48(2H, d, J=8.4), 6.99 (1H, s), 5.67 (2H, s), 5.10 (s, 2H), 1.75 (3H, s).

D. 4-(5-Hydroxymethyl-imidazoyl-1-ylmethyl)-benzonitrile

To the title C compound4-(5-acetoxymethyl-imidazoyl-1-ylmethyl)-benzonitrile hydrobromide (28.9g, 86.0 mmol) in THF:water (3:1, 400 mL) at 0° C. is added lithiumhydroxide (10.8 g, 258 mmol) and the reaction warmed over 3 h andsubsequently stirred at RT for 12 h. The reaction volume is reduced invacuo and the residue is partitioned between EtOAc and saturated aqueoussodium bicarbonate. After washing with brine the combined organic phasesare dried over anhydrous sodium sulfate and concentrated in vacuo toyield a solid which is triturated with diethyl ether to give4-(5-hydroxymethyl-imidazoyl-1-ylmethyl)-benzonitrile: m.p. 162-164° C.;¹H-NMR (DMSO-d₆) δ 7.83 (2H, d, J=8.3), 7.73 (1H, s), 7.30 (2H, d,J=8.3), 6.87(1H, s), 5.35 (2H, s), 5.15 (2H, t, J=5.3), 4.30 (2H, d,J=5.3); e/z (ES) 214 (M+1, 100%).

E.4-(5-t-Butyl-dimethylsilanyloxymethyl-imidazoyl-1-ylmethyl)-benzonitrile

To a solution of the title D compound4-(5-hydroxymethyl-imidazoyl-1-ylmethyl)-benzonitrile (13.6 g, 63.8mmol) in DMF (30 mL) is added imidazole (6.8 g, 100 mmol) followed byTBDMSICI (10.0 g, 66.3 mmol). The reaction mixture is stirred at RT for2 h, then partitioned between EtOAc and saturated aqueous sodiumbicarbonate. The organic solution is dried over anhydrous sodium sulfateand removal of the solvent in vacuo yields a solid which is subjected toflash chromatography (silica gel) eluting with EtOAc to give4-(5-t-butyl-dimethylsilanyloxymethyl-imidazoyl-1-ylmethyl)-benzonitrile:m.p. 77-79° C.; ¹H-NMR (DMSO-d₆) δ7.89 (2H, d, J=8.2), 7.83 (1H, s),7.31 (2H, d, J=8.2), 6.98 (1H, s), 5.42 (2H, s), 4.59 (2H, s), 0.82 (9H,s), 0.00 (6H, s); ¹³C-NMR (DMSO-d₆) δ 164.6, 143.7, 139.5, 132.9, 130.8,128.4, 127.8, 119.0, 110.6, 54.9, 47.5, 26.0, 18.1, −5.2; e/z (ES) 328(M+1, 100%).

F. Methyl[5-(t-butyl-dimethylsilanyloxymethyl)-imidazol-1-yl]-(4-cyano-phenyl)-acetate

To a solution of the title E compound4-(5-t-butyl-dimethylsilanyloxymethyl-imidazoyl-1-ylmethyl)-benzonitrile(10.4 g, 31.8 mmol) in THF (100 mL) at −78° C. is added dropwise 1.0 MLHMDS (67.0 mL, 67.0 mmol) and stirred for 10 min. Methyl cyanoformate(2.55 mL, 31.8 mmol) is added and the solution stirred for 10 min beforequenching the reaction with acetic acid. On warming the reaction mixtureis partioned between ammonium chloride and EtOAc, thereafter thecombined organic phases are dried over anhydrous sodium sulfate andremoval of the solvent in vacuo yields a viscous oil. The crude reactionmixture is subjected to flash chromatography (silica gel) eluting withEtOAc:MeOH:NH₄OH (90:10:0.1) to give the desired material which isre-crystallized from diethyl ether:hexane to give methyl[5-(t-butyl-dimethylsilanyloxymethyl)-imidazol-1-yl]-(4-cyano-phenyl)-acetateas a solid: m.p. 83-84° C.; ¹H-NMR (CDCl₃) δ 7.66 (2H, d, J=8.3), 7.60(1H, s), 7.35 (2H, d, J=8.3), 6.92 (1H, s), 4.63 (1H, d, 13.4), 4.56(1H, d, J=13.4), 3.81 (3H, s), 0.81 (9H, s), 0.00 (3H, s), −0.01 (3H,s); ¹³C-NMR (CDCl₃) δ 168.0, 164.4, 139.4, 137.6, 132.6, 130.2, 128.0,127.5, 117.6, 112.9, 60.3, 54.9, 53.0, 25.4, 17.8, −5.7, −5.8; e/z (ES)386 (M+1, 100%); calculated for C₂₀H₂₇N₃O₃Si, C, 62.31; H, 7.06; N,10.90. found C, 62.36; H, 6.92; N, 11.06.

G. Methyl 1-(4-cyano-phenyl)-(5-hydroxymethyl-imidazol-1-yl)-acetate

The title F compound methyl[5-(t-butyl-dimethylsilanyloxymethyl)-imidazol-1-yl]-(4-cyano-phenyl)-acetate(9.65 g, 25.06 mmol) and p-toluenesulfonic acid (6.0 g, 31.50 mmol) arestirred in MeOH (100 mL) at RT for 24 h. The reaction mixture isevaporated to an oil and partitioned between EtOAc and sodiumbicarbonate. The combined organic phases are dried over anhydrous sodiumsulfate and concentrated in vacuo to yield a solid, which is trituratedwith diethyl ether to give methyl1-(4-cyano-phenyl)-(5-hydroxymethyl-imidazol-1-yl)-acetate: ¹H-NMR(DMSO-d₆) δ 7.92 (2H, d, J=8.3), 7.62 (2H, d, J=8.3), 7.61 (1H, s), 6.83(1H, s), 6.48 (1H, s), 5.26 (1H, t, J=5.3), 4.47 (2H, d, J=5.3), 3.75(3H, s); ¹³C-NMR (DMSO-d₆) δ 168.9, 164.4, 140.6, 137.9, 133.3, 132.1,129.6, 127.0, 118.6, 112.1, 60.3, 53.5, 53.0; e/z (ES) 272 (M+1, 100%).

H. Methyl 1-(4-cyano-phenyl)-(5-formyl-imidazol-1-yl)-acetate

To a solution of the title G compound methyl1-(4-cyano-phenyl)-(5-hydroxymethyl-imidazol-1-yl)-acetate (5.60 g, 20.7mmol) in DCM (100 mL) is added Dess-Martin periodinane (15% wt solution,65 mL, 30 mmol) and the reaction is stirred for 3 h. The reactionmixture is partitioned between EtOAc and sodium bicarbonate-sodiumthiosulfate. The combined organic phases are washed with brine and dried(anhydrous sodium sulfate) and evaporated to a solid. Re-crystallizationfrom EtOAc:hexane gives methyl1-(4-cyano-phenyl)-(5-formyl-imidazol-1-yl)-acetate: m.p. 148-150° C.;¹H-NMR (CDCl₃) δ 9.75 (1H, s), 7.88 (1H, s), 7.78 (2H, d, J=8.3), 7.73(1H, s), 7.51 (2H, d, J=8.3), 6.95 (1H, s), 3.84 (3H, s); ¹³C-NMR(CDCl₃) δ 180.0, 168.4, 165.0, 144.5, 143.3138.5, 133.6, 131.1, 129.6,118.1, 114.3, 62.2, 53.9; e/z (ES) 270 (M+1, 100%); calculated forC₁₄H₁₁N₃O₃, C, 62.45; H 4.12; N, 15.61. found C, 62.13; H, 4.20; N,15.33.

I.4-(7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

To a solution of the title H compound methyl1-(4-cyano-phenyl)-(5-formyl-imidazol-1-yl)-acetate (0.135 g, 0.50 mmol)in DCE (4 mL) is added cyclopropylmethylamine (0.060 mL, 0.70 mmol)followed by sodium triacetoxyborohydride (0.300 g, 1.41 mmol). Thereaction mixture is stirred at RT for 16 h. The reaction is partitionedbetween EtOAc and saturated aqueous sodium bicarbonate and the organicsolution is washed with brine before drying (anhydrous sodium sulfate).The solid obtained after removal of the solvent in vacuo isre-crystallized from acetone:diethyl ether to yield4-(7-cyclopropylmethyl-6-oxo-5,6,7,8tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile:m.p. 146-147° C.; ¹H-NMR (CDCl₃) 7.64 (2H, d, J=8.3), 7.40 (1H, s), 7.07(2H, d, J=8.3), 6.74 (1H, s), 6.07 (1H, s), 4.57 (1H, d, J=16.1), 4.43(1H, d, J=16.1), 3.14 (1H, dd, J=13.8, 10.0), 3.03(1H, dd, J=13.8, 7.2),0.75 (1H, m), 0.19 (2H, m), 0.00 (2H, m); ¹³C-NMR (CDCl₃) δ 164.2,142.7, 135.2, 133.2, 127.7, 123.4, 122.9, 118.7, 111.7, 60.1, 51.0,42.1, 9.2, 3.6, 3.3; e/z (ES) 293 (M+1, 100%); calculated for C₁₇H₁₆N₄O0.15H₂O, C, 69.21; H, 5.57; N, 18.99. found C, 69.10; H, 5.50; N, 19.27.

EXAMPLE 24-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride

The title compound is prepared analogously to Example 1, i.e.,4-(7-methyl-6-oxo-5,6,7,8-tetrahydro-imidazol[1,5-a]pyrazin-5-yl)-benzonitrile,obtained analogously to Example 1, is dissolved in acetone, then treatedwith Et₂O—HCl(g) to afford the hydrochloride salt: m.p. 222-224° C.;¹H-NMR (DMSO-d₆) 9.07 (1H, s), 7.92 (2H, d, J=8.2), 7.48 (1H, s), 7.49(2H, d, J=8.2), 6.46 (1H, s), 4.83 (2H, s), 3.03 (3H, s); ¹³C-NMR(DMSO-d₆) δ 162.5, 140.5, 134.3, 133.4, 128.7, 125.1, 118.6, 115.7,112.4, 60.9, 43.1, 34.9; e/z (ES) 253 (M+1, 100%); calculated forC₁₄H₁₂N₄O HCl 0.4H₂O, C, 56.82; H, 4.70; N, 18.93. found C, 56.88; H,4.54; N, 18.89.

EXAMPLE 34-(7-Benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 163-165°C.; ¹H-NMR (DMSO-d₆) δ 7.89 (2H, d, J=8.3), 7.63 (1H, s), 7.29 (5H, m),7.18 (2H, m), 6.93 (1H, s), 4.73 (1H, d, J=14.9), 4.63 (1H, d, J=16.1),4.56 (1H, d, J=14.9), 4.53 (1H, d, J=16.1); ¹³C-NMR (DMSO-d₆) δ 164.5,142.6, 136.5, 135.3, 133.3, 129.0, 128.0, 127.9, 127.7, 123.5, 122.6,118.7, 111.7, 60.2, 50.0, 41.9; e/z (ES) 329 (M+1, 100%); calculated forC₂₀H₁₆N₄O, C, 73.15; H, 4.91; N, 17.06. found C, 72.83; H, 4.71; N,17.07.

EXAMPLE 44-(7-Allyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 107-109°C.; ¹H-NMR (DMSO-d₆) δ 7.88 (2H, d, J=8.3), 7.62 (1H, s), 7.30 (2 h, d,J=8.3), 6.97 (1H, s), 6.34 (1H, s), 5.73 (1H, m), 5.15 (1H, dd, J=10.3,1.4), 5.09 (1H, dd, J=17.1, 1.4), 4.62 (1H, d, J=16.1), 4.58 (1H, d,J=16.1), 4.12 (1H, dd, J=15.4, 6.4), 3.99 (1H, dd, J=15.4, 5.8); ¹³C-NMR(DMSO-d₆) δ 164.1, 142.6, 135.3, 133.3, 132.3, 127.7, 123.4, 122.7,118.1, 111.7, 60.1, 49.1, 41.7; e/z (ES) 279 (M+1,100%); calculated forC₁₆H₁₄N₄O, C, 69.05; H, 5.07; N, 20.13. found C, 68.84; H, 5.05; N,20.07.

EXAMPLE 54-(6-Oxo-7-propyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 97-98° C.;¹H-NMR (DMSO-d₆) δ 7.87 (2H, d, J=8.3), 7.63 (1H, s), 7.28 (2H, d,J=8.3), 6.96 (1H, s), 6.29 (1H, s), 4.69 (1H, d, J=16.1), 4.59 (1H, d,J=16.1), 3.36 (2H, m), 1.48 (2H, m), 0.75 (3H, t, J=7.4); ¹³C-NMR(DMSO-d₆) δ 164.2, 142.7, 135.3, 133.3, 132.3, 127.6, 123.3, 122.9,118.7, 111.6, 60.1, 48.5, 41.9, 20.0, 11.2; e/z (ES) 281 (M+1, 100%);calculated for C₁₆H₁₆N₄O, C, 68.55; H, 5.75; N, 19.99. found C, 68.30;H, 5.72; N, 19.95.

EXAMPLE 64-(7-Isopropyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 122-124°C.; ¹H-NMR (DMSO-d₆) δ 7.87 (2H, d, J=8.3), 7.64 (1H, s), 7.28 (2H, d,J=8.3), 6.97 (1H, s), 6.28 (1H, s), 4.69 (1H, d, J=16.1), 4.65 (1H, m),4.36 (1H, d, J=16.1), 1.12 (3H, d, J=6.8), 1.07 (3H, d, J=6.8); ¹³C-NMR(DMSO-d₆) δ 163.8, 142.5, 135.2, 133.3, 127.6, 123.4, 123.2, 118.7,111.6, 60.3, 45.3, 35.7, 19.1, 19.0; e/z (ES) 281 (M+1, 100%);calculated for C₁₆H₁₆N₄O, C, 68.55; H, 5.75; N, 19.99. found C, 68.17;H, 5.73; N, 19.89.

EXAMPLE 74-7-[2-(4-Fluoro-phenyl)-ethyl]-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride

The title compound is prepared analogously to Example 2: m.p. 160-162°C.; ¹H-NMR (DMSO-d₆) δ9.12 (1H, s), 7.88 (2H, d, J=8.2), 7.74 (1H, s),7.33 (2H, d, J=8.2), 7.16 (2H, m), 6.98 (2H, m), 6.47 (1H, s), 4.82 (1H,d, J=16.5), 4.61 (1H, d, J=16.5), 3.87 (1H, m), 3.55 (1H, m), 2.82 (2H,m); ¹³C-NMR (DMSO-d₆) δ 162.5, 161.2 (d, J=, 242.2), 139.9, 134.5 (d,J=3.0), 134.4, 133.3, 130.8 (d, J=8.3), 128.2, 125.2, 118.6, 115.8,115.3 (d, J=21.1), 112.3, 61.1, 48.3, 41.4, 31.7; e/z (ES) 361 (M+1,100%); calculated for C₂₁H₁₇N₄OF HCl 0.1 H₂O, C, 63.27; H, 4.35; N,14.05. found C, 63.04; H, 4.46; N, 14.02.

EXAMPLE 84-(7-(3-Morpholin-4-yl-propyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitriledihydrochloride

The title compound is prepared analogously to Example 2: m.p. 246-248°C.; ¹H-NMR (DMSO-d₆) δ 9.13 (1H, s), 7.93 (2H, d, J=8.3), 7.78 (1H, s),7.55 (2H, d, J=8.3), 6.53 (1H, s), 4.91 (2H, s), 3.85 (4H, m), 3.57 (2H,m), 3.33 (2H, m), 3.00 (4H, m), 2.06 (2H, m); ¹³C-NMR (DMSO-d₆) δ 163.1,140.2, 134.3, 133.5, 129.0, 125.2, 118.6, 115.7, 112.4, 63.4, 61.0,53.4, 51.2, 51.1, 44.4, 41.3, 21.0; e/z (ES) 366 (M+1, 100%); calculatedfor C₂₀H₂₃N₅O₂ 2 HCl 0.2H₂O, C, 54.35; H, 5.34; N, 15.85. found C,54.25; H, 5.68; N, 15.84.

EXAMPLE 94-[7-(4-Methoxy-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 155-157°C.; ¹H-NMR (DMSO-d₆) δ 7.88 (2H, d, J=8.3), 7.62 (1H, s), 7.29 (2H, d,J=8.3), 7.14 (2H, d, J=8.6), 6.92 (1H, s), 6.87 (2H, d, J=8.6), 6.39(1H, s), 4.55 (4H, m) 3.72 (3H, s); ¹³C-NMR (DMSO-d₆) δ 164.3, 159.1,142.6, 135.3, 133.3, 129.6, 128.4, 128.0, 127.7, 123.5, 122.6, 118.7,114.4, 111.7, 65.3, 60.1, 55.4, 49.3, 41.5; e/z (ES) 359 (M+1, 100%);calculated for C₂₁H₁₈N₄O₂, C, 70.38; H, 5.06; N, 15.63. found C, 69.98;H, 5.15; N, 15.50.

EXAMPLE 104-[7-(4-Methyl-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 168-170°C.; ¹H-NMR (DMSO-d₆) δ 7.88 (2H, d, 8.3), 7.62 (1H, s), 7.29 (2H, d,J=8.3), 7.11 (2H, d, J=8.2), 7.07 (2H, d, J=8.2), 6.92 (1H, s), 6.40(1H, s), 4.67 (1H, d, J=14.7), 4.59 (1H, d, J=16.2), 4.51 (1H, d,J=14.7), 4.49 (1H, d, J=16.2), 2.26 (3H, s); ¹³C-NMR (DMSO-d₆) δ 164.4,142.6, 137.2, 135.3, 133.5, 133.3, 129.6, 128.1, 127.7, 123.5, 122.6,118.7, 111.7, 60.1, 49.6, 41.7, 21.0; e/z (ES) 343 (M+1, 100%);calculated for C₂₁H₁₈N₄O, C, 73.67; H, 5.30; N, 16.36. found C, 73.54;H, 5.22; N, 16.46.

EXAMPLE 114-[7-(4-Chloro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 2: m.p. 245-246°C.; ¹H-NMR (DMSO-d₆) 9.13 (1H, s), 7.94 (2H, d, J=8.3), 7.70 (1H, s),7.52 (2H, d, J=8.3), 7.41 (2H, d, J=8.4), 7.29 (2H, d, J=8.4), 6.59 (1H,s), 4.77 (1H, d, J=15.1), 4.74 (1H, d, 16.8), 4.72 (1H, d, J=16.8), 4.59(1H, d, J=15.1); ¹³C-NMR (DMSO-d₆) δ 162.6, 139.6, 134.7, 134.0, 133.0,132.2, 129.7, 128.5, 128.3, 124.6, 118.2, 115.4, 112.0, 60.7, 48.9,40.8; e/z (ES) 363 (M+1, 100%); calculated for C₂₀H₁₅N₄OCl HCl, C,60.16; H, 4.04; N, 14.03. found C, 60.17; H, 3.89; N, 14.08.

EXAMPLE 124-[6-Oxo-7-(4-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride

The title compound is prepared analogously to Example 2: m.p. 234-236°C.; ¹H-NMR (DMSO-d₆) δ 9.16 (1H, s), 7.94 (2H, d, J=8.3), 7.72 (2H, d,J=8.0), 7.71 (1H, s), 7.55 (2H, d, J=8.3), 7.48 (2H, d, J=8.0), 6.63(1H, s), 4.90 (1H, d, 15.5), 4.79 (2H, s), 4.70(1H, d, J=15.5); ¹³C-NMR(DMSO-d₆) δ 163.2, 141.1, 140.1, 134.2, 133.4, 128.8, 128.6 (q, J=31.7),125.8 (t, J=3.8), 125.1, 118.6, 115.8, 112.5, 61.2, 49.7, 41.5; e/z (ES)397 (M+1,100%); calculated for C₂₁H₁₅N₄OF₃ HCl, C, 58.27; H, 3.73; N,12.94. found C, 58.06; H, 3.70; N, 12.93.

EXAMPLE 134-[6-Oxo-7-(3-methyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride

The title compound is prepared analogously to Example 2: m.p. 275-277°C.; ¹H-NMR (DMSO-d₆) 9.14 (1H, s), 7.95 (2H, d, J=8.3), 7.70 (1H, s),7.51 (2H, d, J=8.3), 7.23 (1H, d, J=7.6), 7.21 (1H, d, J=7.6), 7.10 (1H,d, J=7.6), 7.02 (1H, d, J=7.6), 6.97 (1H, s), 6.60 (1H, s), 4.69 (4H,m), 2.23 (3H, s); ¹³C (DMSO-d₆) 162.4, 139.7, 137.8, 135.5, 134.0,133.0, 128.5, 128.2, 128.1, 124.8, 124.6, 118.1, 115.4, 112.0, 60.7,49.3, 40.6, 20.8; e/z (ES) 343 (M+1, 100%); calculated for C₂₁H₁₈N₄OHCl, C, 66.57; H, 5.05; N, 14.67. found C, 66.38; H, 5.02; N, 14.84.

EXAMPLE 144-[6-Oxo-7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 132-135°C.; ¹H-NMR (DMSO-d₆) δ 7.88 (2H, d, J=8.2), 7.61 (1H, s), 7.27 (4H, m),7.19 (2H, m,), 6.93 (1H, s), 6.39 (1H, s), 4.64 (4H, m); ¹³C-NMR(DMSO-d₆): δ 164.1, 161.5 (d, J=243.0), 142.1, 134.9, 132.9, 132.4 (d,J=3.0), 129.8 (d, J=8.3), 127.3, 123.0, 122.1, 118.3, 115.4 (d, J=21.1),111.3, 59.7, 48.8, 41.4; e/z 347 (M+1, 100%); calculated C₂₀H₁₅FN₄O0.1H₂O, C, 69.00; H, 4.40; N, 16.09. found C, 68.72; H, 4.35; N, 16.10.

EXAMPLE 154-[6-Oxo-7-(3-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride

The title compound is prepared analogously to Example 2: m.p. 250-252°C.; ¹H-NMR (MeOH-d₄) δ 9.01 (1H, s), 7.83 (2H, d, J=8.1), 7.65 (1H, s),7.61 (1H, d, J=6.3), 7.54 (2H, m), 7.52 (1H, s), 7.49 (2H, d, J=8.1),6.54 (1H, s), 4.93 (1H, d, J=15.0), 4.86 (1H, d, J=16.5), 4.78 (1H, d,J=15.0), 4.72 (1H, d, J=16.5); ¹³C-NMR (MeOH-d₄) δ 164.6, 140.2, 138.3,135.6, 134.4, 133.0, 132.2 (q, J=31.9), 130.9, 129.2, 127.0, 126.0 (d,J=4.0), 125.8 (d, J=4.0), 125.4 (q, J=272.3), 118.8, 116.9, 114.8, 63.1,51.3, 42.3; e/z (ES) 397 (M+1, 100%); calculated for C₂₁H₁₅F₃N₄O HCl, C,58.27; H, 3.73; N, 12.94. found C, 57.91; H, 3.86; N, 12.74.

EXAMPLE 164-[6-Oxo-7-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-imidazol-1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 1: m.p. 175-176°C.; ¹H-NMR (DMSO-d₆) δ 7.89 (2H, d, J=8.0), 7.60 (2H, m), 7.34 (3H, m),7.19 (2H, d, J=8.2), 6.94 (1H, s), 6.40 (1H, s), 4.64 (4H, m); ¹³C-NMR(DMSO-d₆) δ 164.3, 142.0, 137.5, 134.9, 132.9, 131.1, 130.7, 130.1,129.5, 127.9, 127.3, 123.1, 122.0, 118.3, 114.5, 111.4, 59.7, 48.6,41.9; e/z (ES) 397 (M+1, 100%); calculated for C₂₀H₁₄N₄OCl₂, C, 60.47;H, 3.55; N, 14.10. found C, 60.18; H, 3.64; N, 14.07.

EXAMPLE 17

The following compounds are prepared analogously to Example 1.

e/z Example R R′ (M + 1) m.p. (° C.) 17-1  cyclopropyl 4-CN-phenyl 27917-2  cyclohexyl 4-CN-phenyl 321 17-3  cyclopentyl 4-CN-phenyl 307 17-4 2-methoxyethyl 4-CN-phenyl 297 17-5  3-methoxypropyl 4-CN-phenyl 31117-6  4-pyridylmethyl 4-CN-phenyl 330 17-7  4-F-benzyl 4-CF₃-phenyl 390257-258 17-8  cyclopropylmethyl 3-CF₃-phenyI 336 240-242 17-9 4-F-benzyl 4-MeO-phenyl 352 205-206 17-10 4-F-benzyl 2-MeO-phenyl 351134-135 17-11 4-F-benzyl 2-Cl-phenyl 356 160 17-12 4-F-benzyl 1-naphthyl371 17-13 4-F-benzyl 2-naphthyl 371 17-14 4-F-benzyl 2-thienyl 327 95-9717-15 4-F-benzyl 3-thienyl 327

EXAMPLE 18 7-Benzyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

A. 4-(t-Butyidimethylsilanoxymethyl)-1-trityl-1H-imidazole

To a suspension of the title A compound in Example1,1-trityl-4-hydroxymethyl-imidazole (21.8 g, 101 mmol) in DMF (200 mL)is added imidazole (13.1 g, 192.4 mmol), DMAP (0.20 g) followed byTBDMSICI (10.6 g, 70.3 mmol). The reaction mixture is stirred for 18 hat RT before being partitioned between EtOAc and saturated aqueoussodium bicarbonate. The combined organic phases are washed with brine,dried over anhydrous sodium sulfate and then filtered through a silicapad to yield 4-(t-butyldimethylsilanoxy-methyl)-1-trityl-1H-imidazole asa solid after removal of the solvent in vacua: m.p. 90-91° C.; ¹H-NMR(CDCl₃) δ 7.29 (10H, m), 7.13 (6H, m), 6.70 (1H, s), 4.66 (2H, s), 0.82(9H, s), 0.00 (6H, s); e/z (ES) 455 (M+1, 100%).

B. Methyl [5-hydroxymethyl)-imidazol-1-yl]-phenyl-acetate

Under a nitrogen atmosphere is mixed the title B compound,4-(t-butyldimethyl-silanoxymethyl)-1-trityl-1H-imidazole (5.0 g, 11.0mmol) and sodium sulfate (2.0 g, 14.0 mmol) in acetonitrile (20 mL) andstirred at RT. To this mixture is added a solution of methylα-bromo-phenylacetate (2.53 g, 11.0 mmol) in acetonitrile (10 mL) andthe reaction is stirred for 18 h. The mixture is vacuum filtered,treated with saturated HCl solution in MeOH (20 mL) and the mixture isstirred for 3 h. The solution is concentrated in vacuo and the residuetaken up in water and washed with EtOAc. The aqueous solution isbasified with saturated aqueous sodium bicarbonate and extracted intoEtOAc. The combined extracts are washed with brine and dried (anhydroussodium sulfate). The solvent is removed to yield methyl[5-hydroxymethyl)-imidazol-1-yl]-phenyl-acetate as a semi-solid: ¹H-NMR(CDCl₃) δ 7.48-7.27 (6H, m), 6.83 (1H, s), 6.26 (1H, s), 4.59 (2H, s),3.79 (3H, s); e/z (ES) 247 (M+1, 100%).

C. Methyl (5-formyl-imidazol-1-yl)-phenyl-acetate

The title B compound methyl[5-hydroxymethyl)-imidazol-1-yl]-phenyl-acetate (3.14 g, 12.8 mmol) inDCM (30 mL) is added to a solution of Dess-Martin periodinane (15% wtsolution, 35 mL, 30 mmol) and the reaction stirred for 18 h. Thereaction mixture is partitioned between EtOAc and sodiumbicarbonate-sodium thiosulfate. The combined organic phases are washedwith brine and dried (anhydrous sodium sulfate) and evaporated to an oilwhich is chromatographed (silica gel) eluting with hexane:EtOAc (1:1) toyield methyl (5-formyl-imidazol-1-yl)-phenyl-acetate as a solid: m.p.106-109° C.; ¹H-NMR (CDCl₃) δ 9.78 (1H, s), 7.86 (1H, s), 7.37-7.52 (6H,m), 6.71 (1H, s), 3.82 (3H's, s); e/z (ES) 245 (M+1, 100%).

D. 7-Benzyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

To a solution of the title C compound, methyl1-phenyl-(5-formyl-imidazol-1-yl)-acetate (0.45 g, 1.80 mmol) in1,2-dichloroethane (15 mL) is added benzylamine (0.21 g, 2.0 mmol)followed by sodium triacetoxyborohydride (0.850 g, 4.00 mmol). Thereaction mixture is stirred at 40° C. for 16 h. The reaction ispartitioned between EtOAc and saturated aqueous sodium bicarbonate andthe organic solution is washed with brine before drying (anhydroussodium sulfate). The product obtained after removal of the solvent invacuo is dissolved in acetone, treated with Et₂O—HCl(g) to yield7-benzyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one hydrochloride:m.p. 249-251° C.; ¹H (DMSO-d₆) 9.16 (1H, s), 7.68 (1H, s), 7.46 (3H, m),7.30 (7H, m), 6.45 (1H, s), 4.78 (1H, d, J=15.0), 4.76 (1H, d, J=15.0),4.65 (2H, d, J=15.0); ¹³C (DMSO-d₆) 163.7, 136.2, 134.3, 129.6, 129.5,129.0, 128.1, 128.0, 127.2, 125.1, 115.7, 61.6, 49.9, 41.1; e/z (ES) 304(M+1, 100%); calculated for C₁₉H₁₇N₃O HCl, C, 67.15; H, 5.34; N, 12.37.found C, 66.88; H, 5.29; N, 12.12.

EXAMPLE 19 7-Methyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 252-254°C.; ¹H-NMR (DMSO-d₆) δ 9.16 (1H, s), 7.74 (1H, s), 7.42 (3H, m), 7.27(2H, m), 6.34 (1H, s), 4.83 (2H, s), 3.04 (3H, s); ¹³C-NMR (DMSO-dr) δ163.2, 135.7, 134.1, 129.6, 129.5, 127.3, 125.1, 115.4, 61.3, 43.1,34.8; e/z (ES) 228 (M+1, 100%); calculated for C₁₃H₁₃N₃O HCl, C, 59.21;H, 5.35; N, 15.93. found C, 58.85; H, 5.02; N, 15.76.

EXAMPLE 205-(4-Bromo-phenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: m.p. 143-144°C.; ¹H-NMR (DMSO-d₆) δ 7.50 (3H, m), 7.07 (2 h, d, J=8.4), 6.93 (1H, s),6.13 (1H, s), 4.66 (2H, s), 2.98 (3H, s); ¹³C-NMR (DMSO-d₆) δ 164.6,137.3, 135.1, 132.2, 129.0, 123.1, 122.0, 59.7, 43.9, 34.7; e/z (ES)306/308 (M+1, 100%); calculated for C₁₃H₁₂N₃OBr, C, 51.00; H, 3.95; N,13.73. found C, 50.65; H, 3.97; N, 13.57.

EXAMPLE 215-(4-Bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: m.p. 123-124°C.; ¹H-NMR (DMSO-d₆) 7.61 (1H, s), 7.59 (2H, d, J=8.4), 7.14 (2H, d,J=8.6), 7.06 (2H, d, J=8.4), 6.89 (1H, s), 6.88 (2H, 2H, d, J=8.6), 6.24(1H, s), 4.65 (1H, d, J=14.5), 4.58 (1H, d, J=16.1), 4.48 (1H, d,J=14.5), 4.45 (1H, d, J=16.1), 3.72 (3H, s); ¹³C-NMR (DMSO-d₆) δ 164.4,158.6, 136.4, 134.8, 131.8, 129.2, 128.4, 128.0, 122.9, 121.7, 113.9,59.4, 54.9, 48.8, 41.06; e/z (ES) 411/413 (M+1, 100%); calculated forC₂₀H₁₈N₃O₂Br, C, 58.20; H, 4.40; N, 10.19. found C, 58.08; H, 4.43; N,10.09.

EXAMPLE 225-(4-Bromo-phenyl)-7-cyclopropylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 223-225°C.; ¹H-NMR (DMSO-d₆) δ 9.18 (1H, s), 7.75 (1H, s), 7.65 (2H, d, J=8.4),7.27 (2H, d, J=8.4), 6.39 (1H, s), 4.95 (1H, d, J=16.6), 4.81 (1H, d,J=16.6), 3.45 (1H, dd, J=13.8, 7.0), 3.32 (1H, dd, J=13.8, 7.0), 1.05(1H, m), 0.47 (2H, m), 0.27 (2H, m); ¹³C-NMR (DMSO-d₆) δ 162.5, 134.2,133.8, 132.0, 129.2, 125.0, 122.5, 115.0, 60.4, 50.6, 40.8, 8.6, 3.2,2.9; e/z (ES) 346/348 (M+1, 100%); calculated for C₁₆H₁₆N₃OBr HCl, C,50.22; H, 4.48; N, 10.98. found C, 50.00; H, 4.34; N, 10.76.

EXAMPLE 237-Benzyl-S-(4-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 250° C.(dec.); ¹H-NMR (DMSO-d₆) δ 9.02 (1H, s), 7.67 (3H, m), 7.30 (7H, m),6.42 (1H, s), 4.70 (4H, m); ^(—)C-NMR (DMSO-d₆) δ 163.0, 135.7, 134.2,134.0, 132.0, 129.3, 128.6, 127.6, 124.6, 122.6, 115.6, 60.6, 49.5,40.7; e/z (ES) 382/384 (M+1, 100%); calculated for C₁₉H₁₆N₃OBr, C,54.50; H, 4.09; N, 10.04. found C, 54.05; H, 3.99; N, 9.97.

EXAMPLE 245-(4-Bromo-phenyl)-7-(4-chloro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 158-159°C.; ¹H-NMR (DMSO-d₆) δ 7.61 (1H, s), 7.59 (2H, d, J=8.5), 7.38 (2H, d,J=8.4), 7.23 (2H, d, J=8.4), 7.07 (2H, d, J=8.5), 6.91 (1H, s), 6.25(1H, s), 4.72 (1H, d, J=15.0), 4.62 (1H, d, J=16.0), 4.54 (1H, d,J=15.0), 4.53 (1H, d, J=16.0); ¹³C-NMR (DMSO-d₆) δ 162.6, 134.4, 133.3,132.8, 130.8, 129.8, 127.5, 126.5, 126.4, 120.9, 120.0, 119.7, 57.4,46.8, 39.5; e/z (ES) 418/420 (M+1, 100%); calculated for C₁₉H₁₅N₃OBrCl,C, 54.76; H, 3.63; N, 10.08. found C, 54.87; H, 3.64; N, 9.99.

EXAMPLE 255-(4-Bromo-phenyl)-7-(4-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 113-114°C.; ¹H-NMR (DMSO-d₆) δ 7.69 (2H, d, J=8.0), 7.61 (2H, d, J=8.0), 7.60(1H, s), 7.41 (2H, d, J=8.0), 7.09 (2H, d, J=8.3), 6.92 (1H, s), 6.28(1H, s), 4.84 (1H, d, J=15.3), 4.67 (1H, d, J=16.0), 4.64 (1H, d,J=16.0), 4.59 (1H, d, J=15.3); ¹³C-NMR (DMSO-d₆) δ 164.8, 141.2, 136.3,134.9, 131.8, 128.5, 128.2, 127.8, 125.4, 124.1 (q, J=271.7), 122.9,122.1, 121.8, 59.5, 49.2, 41.9; e/z (ES) 450/452 (M+1, 100%); calculatedfor C₂₀H₁₅N₃OBrF₃, C, 53.35; H, 3.36; N, 9.33. found C, 53.25; H, 3.29;N, 9.22.

EXAMPLE 265-(4-Bromo-phenyl)-7-(4-methoxy-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 149-150°C.; ¹H-NMR (DMSO-d₆) δ 7.68 (1H, s), 7.63 (2H, d, J=8.4), 7.25 (2H, d,J=8.9), 7.16 (2H, d, J=8.4), 6.97 (2H, d, J=8.9), 6.96 (1H, s), 6.31(1H, s), 5.02 (1H, d, J=15.7), 4.88 (1H, d, J=15.7), 3.76 (3H, s);¹³C-NMR (DMSO-d₆) δ 165.0, 158.3, 136.6, 135.3, 134.7, 132.3, 129.0,127.4, 123.4, 123.0, 122.2, 114.5, 60.4, 55.7, 45.7; e/z (ES) 398/400(M+1, 100%); calculated for C₁₉H₁₆N₃OBr, C, 57.30; H, 4.05; N, 10.55.found C, 57.02; H, 4.03; N, 10.37.

EXAMPLE 27S-(4-Bromo-phenyl)-7-(4-fluoro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 136-138°C.; ¹H-NMR (DMSO-d₆) δ 9.14 (1H, s), 7.72 (1H, s), 7.61 (2H, d, J=8.4),7.18 (2H, dd, J=8.6, 5.7), 7.10 (2H, d, J=8.4), 7.00 (2H, app t J=8.9),6.35 (1H, s), 4.82 (1H, d, J=16.5), 4.60 (1H, d, J=16.5), 3.88 (1H, m),3.55 (1H, m), 2.80 (2H, m); ¹³C-NMR (DMSO-d₆) δ 162.5, 160.8 (d,J=241.5), 134.3, 134.2, 133.8, 131.9, 130.4 (d, J=8.3), 128.9, 124.8,122.4, 115.1, 114.9 (d, J=21.1), 60.5, 48.0, 41.0, 31.3; e/z (ES)414/416 (M+1, 100%); calculated for C₂₀H₁₇N₃OFBr HCl, C, 53.29; H, 4.02;N, 9.32. found C, 52.97; H, 4.10; N, 9.20.

EXAMPLE 285-(4-Bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 205-207°C.; ¹H-NMR (DMSO-d₆) δ 9.12 (1H, s), 7.67 (1H, s), 7.64 (2H, d, J=8.5),7.32 (2H, dd, J=8.5, 5.6), 7.25 (2H, d, J=8.5), 7.21 (2H, app t, J=8.9),6.44 (1H, s), 4.78 (1H, d, J=14.7), 4.75 (1H, d, J=16.8), 4.67 (1H, d,J=16.8), 4.60 (1H, d, J=14.7); ¹³C-NMR (DMSO-d₆) δ 163.4, 162.0 (d,J=243.0), 134.5, 134.4, 132.5, 132.4, 130.4 (d, J=8.3), 129.8, 125.1,123.0, 115.8, 115.7 (d, J=21.3), 61.0, 48.9, 41.1; e/z (ES) 400/402(M+1, 100%); calculated for C₁₉H₁₅N₃ObrF HCl, C, 52.26; H, 3.69; N,9.62. found C, 52.53; H, 3.75; N, 9.50.

EXAMPLE 295-(3-Bromo-phenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 265° C.(dec.); ¹H-NMR (DMSO-d₆) δ9.12 (1H, s), 7.74 (1H, s), 7.65 (1H, d,J=8.0), 7.57 (1H, s), 7.39 (1H, t, J=8.0), 7.24 (1H, d, J=8.0), 6.36(1H, s), 4.83 (2H, m), 3.04 (3H, s); ¹³C-NMR (DMSO-d₆) δ 162.3, 137.6,133.7, 132.1, 130.3, 126.1, 124.7, 122.1, 114.9, 60.1, 42.7, 34.5; e/z(ES) 306/308 (M+1, 100%); calculated for C₁₃H₁₂N₃OBr HCl, C, 45.57; H,3.83; N, 12.26. found C, 45.72; H, 3.98; N, 11.78.

EXAMPLE 305-(3-Bromo-phenyl)-7-cyclohexyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-oneoxalate

The title compound is prepared analogously to Example 18: m.p. 129-131°C.; ¹H-NMR (DMSO-d₆) 7.86 (1H, s), 7.58 (1H, d, J=7.9), 7.36 (2H, m),7.07 (2H, m), 6.20 (1H, s), 4.74 (1H, d, J=16.2), 4.40 (1H, d, J=16.2),4.26 (1H, m), 1.77-1.09 (10H, m); ¹³C-NMR (DMSO-d₆) 164.0, 161.8, 139.5,135.0, 131.8, 131.6, 129.6, 125.5, 123.6, 122.4, 60.1, 53.4, 36.7, 29.2,28.8, 25.5, 25.4, 25.2; e/z (ES) 374/376 (M+1, 100%); calculated forC₁₈H₂₀N₃OBr C₂H₂O₄, C, 51.74; H, 4.78; N, 9.05. found C, 51.43; H, 4.64;N, 8.94.

EXAMPLE 315-(4-Bromo-phenyl)-7-(4-methoxy-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-oneoxalate

The title compound is prepared analogously to Example 18: m.p. 186-189°C.; ¹H-NMR (DMSO-d₆) δ 7.87 (1H, s), 7.61 (1H, d, J=7.9), 7.44 (1H, s),7.40 (1H, t, J=7.9), 7.27 (2H, d, J=8.8), 7.20 (1H, d, J=7.9), 7.07 (1H,s), 6.98 (2H, d, J=8.8), 6.35 (1H, s), 5.08 (1H, d, J=15.9), 4.91 (1H,d, J=15.9), 3.77 (3H, s); ¹³C-NMR (DMSO-d₆) 8164.7, 161.8, 158.4, 139.5,134.7, 131.9, 131.6, 129.9, 127.4, 125.8, 122.5, 114.5, 60.4, 55.7,45.6; e/z (ES) 398/400 (M+1, 100%); calculated for C₁₈H₁₆N₃O₂Br C₂H₂O₄,C, 51.65; H, 3.72; N, 8.61. found C, 51.49; H, 3.62; N, 8.40.

EXAMPLE 325-(3-Bromo-phenyl)-7-cyclopropylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 249-250°C.; ¹H-NMR (DMSO-d₆) δ 9.19 (1H, s), 7.75 (1H, s), 7.65 (1H, d, J=7.9),7.59 (1H, s), 7.41 (1H, t, J=7.9), 7.28 (1H, d, J=7.9), 6.40 (1H, s),4.95 (1H, d, J=16.9), 4.85 (1H, d, j 16.9), 3.45 (1H, dd, J=14.0, 7.3),3.35 (1H, dd, J=14.0, 7.3), 1.03 (1H, m), 0.48 (2H, m), 0.27 (2H, m);¹³C-NMR (DMSO-d₈) δ 162.4, 137.3, 133.8, 132.1, 131.4, 130.2, 126.0,124.9, 122.2, 115.0, 60.2, 50.7, 40.9, 8.7, 3.2, 3.0; e/z (ES) 346/348(M+1, 100%); calculated for C₁₆H₁₆N₃OBr HCl, C, 50.22; H, 4.48; N,10.98. found C, 49.93; H, 4.48; N, 10.74.

Separation of the enantiomers of the free base may be achieved using aChiralpak AD HPLC column under isocratic conditions(isopropanol:hexane—20:80); Retention times 18.5 and 27.6 min.

EXAMPLE 337-Benzyl-5-(3-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 249-251°C.; ¹H-NMR (DMSO-d₆) δ 9.10 (1H, s), 7.67 (2H, d, J=6.0), 7.57 (1H, s),7.36 (7H, m), 6.46 (1H, s), 4.72 (4H, m); ¹³C-NMR (DMSO-d₈) 8162.8,137.3, 135.7, 134.0, 132.1, 131.3, 130.1, 128.6, 127.7, 127.6, 126.1,124.6, 122.2, 115.4, 60.4, 49.6, 40.8; e/z (ES) 382/384 (M+1, 100%);calculated for C₁₈H₁₆N₃OBr HCl, C, 54.50; H, 4.09; N, 10.04. found C,54.47; H, 4.09; N, 10.01.

Separation of the enantiomers may be achieved using a Chiralpak AD HPLCcolumn under isocratic conditions (isopropanol:hexane—20:80); Retentiontimes 26.8 and 29.6 min.

EXAMPLE 345-(3-Bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 246-248°C.; ¹H-NMR (DMSO-d₆) δ9.16 (1H, s), 7.68 (1H, s), 7.65 (1H, d, J=7.9),7.56 (1H, s), 7.40 (1H, t, J=7.9), 7.25 (1H, d, J=7.9), 7.22 (2H, d,J=8.8), 6.90 (2H, d, J=8.8), 6.45 (1H, s), 4.73 (1H, d, J=16.6), 4.71(1H, d, J=14.6), 4.64 (1H, d, J=16.6), 4.58 (1H, d, J=14.6), 3.74 (3H,s); ¹³C-NMR (DMSO-d₈) δ 163.0, 159.2, 137.7, 134.3, 132.6, 131.7, 130.6,129.8, 128.0, 126.5, 125.1, 122.6, 115.6, 114.4, 60.8, 55.5, 49.4, 40.8;e/z (ES) 412/414 (M+1, 100%); calculated for C₂₀H₁₈N₃O₂Br HCl, C, 53.53;H, 4.27; N, 9.36. found C, 53.22; H, 4.38; N, 9.16.

EXAMPLE 355-(3-Bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 246-248°C.; ¹H-NMR (DMSO-d₆) δ 9.16 (1H, s), 7.66 (2H, m), 7.57 (1H, s), 7.29(6H, m), 6.45 (1H, s), 4.76 (1H, d, J=, 15.0), 4.73 (2H, s), 4.62 (1H,d, J=15.0); ¹³C-NMR (DMSO-d₆) δ 163.2, 162.0 (d, J=242.3), 137.7, 134.3,132.6, 132.4, 132.3, 131.7, 130.6, 130.4 (d, J=8.3), 126.6, 125.0,122.6, 115.8 (d, J=, 18.2), 60.8, 49.3, 41.1; e/z (ES) 400/402 (M+1,100%); calculated for C₁₉H₁₅N₃OBrF HCl, C, 52.26; H, 3.69; N, 9.62.found C, 52.11; H, 3.60; N, 9.56.

EXAMPLE 365-(3-Bromo-phenyl)-7-(4-chloro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 268-270°C.; ¹H-NMR (DMSO-d₆) δ 9.13 (1H, s), 7.66 (2H, m), 7.57 (1H, s), 7.33(6H, m), 6.45 (1H, s), 4.80 (1H, d, J=15.1), 4.74 (2H, s), 4.62 (1H, d,J=15.1); ¹³C-NMR (DMSO-d₆) δ 163.3, 137.6, 135.2, 134.3, 132.7, 132.6,131.7, 130.7, 130.2, 129.0, 126.6, 125.0, 122.6, 115.7, 60.8, 49.4,41.3; e/z (ES) 416/418 (M+1, 100%); calculated for C₁₉H₁₅N₃OCl HCl, C,50.36; H, 3.56; N, 9.27. found C, 50.10; H, 3.56; N, 9.17.

EXAMPLE 37 5-(3-Bromo-phenyl7-(4-methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 265-267°C.; ¹H-NMR (DMSO-d₆) δ 9.08 (1H, s), 7.66 (1H, d, J=7.9), 7.65 (1H, s),7.55 (1H, s), 7.40 (1H, t, J=7.9), 7.25 (1H, d, J=7.9), 7.15 (4H, m),6.44 (1H, s), 4.73 (1H, d, J=14.7), 4.71 (1H, d, J=15.9), 4.65 (1H, d,J=15.9), 4.61 (1H, d, J=14.7), 2.28 (3H, s); ¹³C-NMR (DMSO-d₆) δ 163.1,137.7, 137.3, 134.4, 133.1, 132.6, 131.7, 130.5, 129.6, 128.2, 126.5,125.0, 122.6, 116.0, 60.7, 49.7, 41.0, 21.0; e/z (ES) 396/398 (M+1,100%); calculated for C₂₀H₁₈N₃OBr HCl, C, 55.51; H, 4.43; N, 9.71. foundC, 55.48; H, 4.46; N, 9.66.

EXAMPLE 385-(3-Bromo-phenyl)-7-(4-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 269-271°C.; ¹H-NMR (DMSO-d₆) δ 9.12 (1H, s), 7.71 (2H, d, J=8.2), 7.68 (1H, s),7.66 (1H, d, J=7.9), 7.58 (1H, s), 7.51 (2H, d, J=8.2), 7.41 (1H, t,J=7.9), 6.47 (1H, s), 4.92 (1H, d, J=15.4), 4.79 (2H, s), 4.71 (1H, d,J=15.4); ¹³C-NMR (DMSO-d) δ 163.5, 141.2, 137.6, 132.6, 131.7, 130.7,128.9, 128.4, 126.6, 125.9 (q, J=3.8), 125.0, 122.6, 115.8, 60.9, 49.8,41.6; e/z (ES) 450/452 (M+1, 100%); calculated for C₁₉H₁₅N₃OBrF₃ HCl, C,49.35; H, 3.31; N, 8.63. found C, 49.32; H, 3.34; N, 8.51.

EXAMPLE 395-(3-Bromo-phenyl)-7-(3-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 246-248°C.; ¹H-NMR (DMSO-d₆) δ 9.10 (1H, s), 7.63 (7H, m), 7.40 (1H, t, J=7.9),7.26 (1H, d, J=7.9), 6.46 (1H, s), 4.80 (4H, m); ¹³C-NMR (DMSO-dB) δ163.5, 137.8, 137.7, 134.4, 132.6, 132.2, 131.7, 130.6, 130.1, 129.9,127.8 (q, 248.3), 126.4, 125.0, 124.7 (q, J=3.8), 122.6, 115.9, 60.8,49.7, 41.6; e/z (ES) 450/452 (M+1, 100%); calculated for C₁₉H₁₅N₃OBrF₃HCl C, 49.35; H, 3.31; N, 8.63. found C, 49.33; H, 3.19; N, 8.54.

EXAMPLE 405-(3-Bromo-phenyl)-7-(3-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 240-243°C.; ¹H-NMR (DMSO-d₆) δ 9.12 (1H, s), 7.68 (1H, s), 7.66 (1H, d, J=7.9),7.59 (1H, s), 7.41 (1H, t, J=7.9), 7.38 (1H, t, J=7.6), 7.28 (1H, d,J=7.9), 7.15 (3H, m), 6.45 (1H, s), 4.82 (1H, d, J=15.1), 4.76 (2H, m),4.65 (1H, d, J=15.1); ¹³C-NMR (DMSO) 163.4, 162.7 (d, J=237.3), 139.1(d, J=6.8), 137.6, 134.4, 132.6, 131.7, 131.0 (d, J=6.8), 130.6, 126.6,125.0, 124.2 (d, J=2.3), 122.6, 115.8, 114.8 (d, J=21.8), 60.9, 49.6,41.4; e/z (ES) 400/402 (M+1, 100%); calculated for C₁₉H₁₅N₃OFBr HCl, C,52.26; H, 3.69; N, 9.62. found C, 52.19; H, 3.45; N, 9.52.

EXAMPLE 415-(3-Bromo-phenyl)-7-(3-methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 248-249°C.; ¹H-NMR (DMSO-d₆) δ 9.13 (1H, s), 7.67 (1H, s), 7.66 (1H, d, J=7.9),7.57 (1H, s), 7.41 (1H, t, J=7.9), 7.26 (1H, d, J=7.9), 7.23 (1H, t,J=7.6), 7.11 (1H, d, J=7.6), 7.05 (1H, d, J=7.6), 7.01 (1H, s), 6.47(1H, s), 4.74 (1H, d, J=16.5), 4.68 (2H, s), 4.66 (1H, d, J=16.5), 2.25(3H, s); ¹³C-NMR (DMSO-d₆) δ 163.1, 138.2, 137.8, 136.0, 134.4, 132.6,131.7, 130.4, 128.9, 128.7, 128.6, 126.4, 125.3, 125.0, 122.6, 115.8,60.8, 49.9, 41.2, 21.3; e/z (ES) 396/398 (M+1, 100%); calculated forC₂₀H₁₈N₃OBr HCl, C, 55.51; H, 4.43; N, 9.71. found C, 55.75; H, 4.41; N,9.68.

EXAMPLE 425-(3-Bromo-phenyl)-7-(phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 205-207°C.; ¹H-NMR (DMSO-d₆) δ9.12 (1H, s), 7.69 (1H, s), 7.66 (1H, d, J=8.0),7.46 (1H, s), 7.38 (1H, t, J=7.9), 7.16 (6H, m), 6.37 (1H, s), 4.79 (1H,d, J=17.0), 4.59 (1H, d, J=17.0), 3.83 (1H, m), 3.60 (1H, m), 2.84 (2H,m); ¹³C-NMR (DMSO-dr) δ 162.8, 138.6, 137.5, 134.4, 132.5, 131.7, 130.3,129.0, 128.7, 126.7, 126.1, 125.2, 122.6, 115.6, 60.8, 48.8, 41.7, 32.6;e/z (ES) 396/398 (M+1, 100%); calculated for C₂₀H₁₈N₃OBr HCl, C, 55.51;H, 4.43; N, 9.71. found C, 55.31; H, 4.23; N, 9.68.

EXAMPLE 435-(3-Bromo-phenyl)-7-(4-methoxy-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 202-204°C.; ¹H-NMR (DMSO-d₆) 89.13 (1H, s), 7.69 (1H, s), 7.65 (1H, d, J=9.1),7.46 (1H, s), 7.37 (1H, t, J=7.9), 7.08 (1H, d, J=8.3), 7.03 (2H, d,J=8.7), 6.77 (2H, d, J=8.7), 6.36 (1H, s), 4.78 (1H, d, J=16.5), 4.56(1H, d, J=16.5), 8.85 (1H, m), 3.71 (3H, s), 3.55 (1H, m), 2.77 (2H, m);¹³C-NMR (DMSO-d₆) δ 162.7, 158.1, 137.5, 134.3, 132.4, 131.7, 130.3,130.2, 130.0, 126.1, 125.2, 122.6, 115.6, 114.1, 60.8, 55.3, 48.9, 41.7,31.7; e/z (ES) 426/428 (M+1, 100%); calculated for C₂₁H₂₀N₃O₂Br HCl 0.25H₂O, C, 53.98; H, 4.64; N, 8.99. found C, 53.92; H, 4.47; N, 8.93.

EXAMPLE 445-(3-Bromo-phenyl)-7-(4-chloro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 225-226°C.; ¹H-NMR (DMSO-d₆) 9.12 (1H, s), 7.72 (1H, s), 7.65 (1H, d, 7.9), 7.44(1H, s), 7.36 (1H, t, J=7.9), 7.23 (2H, d, J=8.6), 7.17 (2H, d, J=8.6),7.06 (d, J=7.5), 6.35 (1H, s), 4.82 (1H, d, J=16.5), 4.66 (1H, d,J=16.5), 3.88 (1H, m), 3.58 (1H, m), 2.85 (2H, m); ¹³C-NMR (DMSO-d₆)162.8, 137.6, 137.4, 134.3, 132.4, 131.6, 131.3, 130.9, 130.3, 128.6,126.1, 125.2, 122.6, 115.6, 60.8, 48.2, 41.5, 31.8; e/z (ES) 432/434(M+1, 100%); calculated for C₂₀H₁₇N₃OBrCl HCl, C, 51.42; H, 3.88; N,8.99. found C, 51.14; H, 3.55; N, 8.98.

EXAMPLE 455-(3-Bromo-phenyl)-7-(3-chloro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 184-186°C.; ¹H-NMR (DMSO-d₆) δ 9.09 (1H, s), 7.71 (1H, s), 7.64 (1H, d, J=7.9),7.45 (1H, s), 7.36 (1H, t, J=7.9), 7.24 (3H, m), 7.10 (2H, m), 6.35 (1H,s), 4.81 (1H, d, J=16.6), 4.67 (1H, d, J=16.6), 3.85 (1H, m), 3.62 (1H,m), 2.86 (2H, m); ¹³C-NMR (DMSO-d₆) δ 162.4, 140.8, 136.9, 133.9, 132.8,132.0, 131.2, 130.0, 129.9, 128.5, 127.4, 126.3, 125.6, 124.8, 122.2,115.2, 60.3, 47.7, 41.0, 31.7; e/z (ES) 430/432 (M+1, 100%); calculatedfor C₂₀H₁₇N₃OBrCl HCl, C, 51.42; H, 3.88; N, 8.99. found C, 51.33; H,3.70; N, 8.85.

EXAMPLE 465-(3-Bromo-phenyl)-7-(4-methyl-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 197-199°C.; ¹H-NMR (DMSO-d₆) δ 9.11 (1H, s), 7.69 (1H, s), 7.66 (1H, d, J=9.1),7.44 (1H, s), 7.37 (1H, m), 7.08 (1H, d, J=7.5), 7.01 (4H, s), 6.36 (1H,s), 4.78 (1H, d, J=16.6), 4.56 (1H, d, J=16.6), 3.87 (1H, m), 3.56 (1H,m), 2.79 (2H, m), 2.24 (3H, s); ¹³C-NMR (DMSO-d₆) δ 162.8, 137.4, 135.6,135.4, 134.3, 132.4, 131.6, 130.2, 129.3, 128.9, 126.1, 125.2, 122.6,115.6, 60.8, 48.8, 41.6, 32.2, 21.0; e/z (ES) 410/412 (M+1, 100%);calculated for C₂₁H₂₀N₃OBr HCl, C, 56.46; H, 4.74; N, 9.41. found C,56.36; H, 4.50; N, 9.29.

EXAMPLE 475-(3-Bromo-phenyl)-7-(4-fluoro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 179-180°C.; ¹H-NMR (DMSO-d₆) δ 9.09 (1H, s), 7.70 (1H, s), 7.64 (1H, d, J=9.0),7.43 (1H, s), 7.43 (1H, t, J=7.9), 7.17 (2H, dd, J=8.7, 5.6), 7.02 (3H,m), 6.35 (1H, s), 4.80 (1H, d, J=16.9), 4.63 (1H, d, J=16.9), 3.86 (1H,m), 3.57 (1H, m), 2.84 (2H, m); ¹³C-NMR (DMSO-d₆) δ 162.4, 160.9 (d,J=242.0), 137.0, 134.3, 133.9, 132.0, 131.2, 130.4 (d, J=8.0), 129.8,125.6, 124.7, 122.1, 115.2, 114.9 (d, J=21.1), 60.3, 48.1, 41.1, 31.3;e/z (ES) 414/416 (M+1, 100%); calculated for C₂₀H₁₇N₃OBrF HCl, C, 53.29;H, 4.02; N, 9.32. found C, 53.02; H, 3.73; N, 9.32.

EXAMPLE 485-(3-Bromo-phenyl)-7-thiophen-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 233-235°C.; ¹H-NMR (DMSO-d₆) 89.11 (1H, s), 7.70 (1H, s), 7.66 (1H, d, J=9.0),7.54 (1H, s), 7.50 (1H, d, J=5.2), 7.39 (1H, t, J=7.7), 7.23 (1H, d,J=7.9), 7.14 (1H, d, 2.6), 7.01 (1H, dd, J=5.2, 3.6), 6.45 (1 h, s),4.81 (4H, m); ¹³C-NMR (DMSO-d₆) δ 162.88, 137.97, 137.56, 134.42,132.57, 131.69, 130.54, 128.19, 127.18 (d, J=5.1), 126.44, 124.89,122.57, 116.00, 60.65, 45.00; e/z (ES) 388/390 (M+1, 100%); calculatedfor C₁₇H₁₄BrN₃OS HCl, C, 48.07; H, 3.56; N, 9.89. found C, 48.12; H,3.44; N, 9.81.

EXAMPLE 495-(3-Bromo-phenyl)-7-furan-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 18: m.p. 215-218°C.; ¹H-NMR (DMSO-d₆) δ 9.14 (1H, s), 7.70 (1H, s), 7.66 (2H, m), 7.57(1H, s), 7.40 (1H, t, J=7.7), 7.26 (1H, d, J=7.9), 6.44 (3H, s), 4.73(4H, m); ¹³C-NMR (DMSO) δ 162.44, 148.86, 143.22, 137.11, 133.88,132.13, 131.27, 130.15, 126.11, 124.45, 122.14, 115.39, 110.52, 109.32,60.26, 42.53, 40.68; e/z (ES) 372 (M+1, 100%); calculated forC₁₇H₁₄BrN₃O₂ HCl, C, 49.96; H, 3.70; N, 10.28. found C, 50.16; H, 3.66;N, 10.32.

EXAMPLE 505-(3-Bromo-phenyl)-7-thiophen-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: m.p. 43-45°C.; ¹H-NMR (CDCl₃) δ 7.50 (2H, d, J=9.0), 7.30-7.21 (3H, m), 7.12 (1H,d, J=3.0), 7.05-7.00 (2H, m), 6.90 (1H, d, J=3.0), 5.91 (1H, s), 4.76(1H, d, J=15.0), 4.62 (1H, d, J=15.0), 4.53-4.40 (2H, m); ¹³C-NMR(CDCl₃) 5164.5, 137.9, 135.9, 135.0, 132.2, 130.7, 129.0, 127.2, 127.1,124.6, 124.1, 123.6, 123.4, 122.0, 60.6, 45.9, 41.7; MS (m/z) 388.0(M+1, 100%); calculated for C₁₇H₁₄BrN₃OS, C, 52.59; H, 3.63; N, 10.82.found C, 52.34; H, 3.71; N, 10.57.

EXAMPLE 515-(3-Bromo-phenyl)-7-furan-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: ¹H-NMR(DMSO-d₆) δ 7.63-7.56 (m, 4H), 7.36 (d, J=7.9, 1H), 7.31 (d, J=2.5, 1H),7.06 (d, J=7.9, 1H), 6.92 (s, 1H), 6.30 (s, 1H), 6.22 (s, 1H), 4.68-4.41(m, 4H); ¹³C-NMR (DMSO-d₆) δ 164.1, 143.8, 141.1, 139.6, 134.8, 131.3,131.1, 129.1, 125.1, 122.9, 122.1, 121.9, 119.8, 110.2, 59.2, 41.1,40.7; MS (m/z) 372.0 (M+1, 100%); calculated for C₁₇H₁₄BrN₃O₂, C, 54.86;H, 3.79; N, 11.29. found C, 54.77; H, 3.91; N, 11.11.

EXAMPLE 525-(3-Bromo-phenyl)-7-pyridin-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: m.p. 50-54°C.; ¹H-NMR (CDCl₃) δ 8.56 (dd, J=4.8, J=1.5, 1H), 8.50 (d, J=2.1, 1H),7.54-7.50 (m, 3H), 7.26-7.22 (m, 3H), 7.04-7.01 (m, 2H), 5.95 (s, 1H),4.81 (d, J=15.0, 1H), 4.60 (d, J=15.0, 1H), 4.48 (s, 2H); ¹³C-NMR(CDCl₃) 5164.9, 149.8, 149.4, 137.6, 135.8, 135.1, 132.3, 131.1, 130.8,128.9, 124.5, 124.3, 124.0, 123.4, 121.6, 60.5, 48.4, 41.9; MS (m/z)383.2 (M+1, 100%); calculated for C₁₈H₁₅BrN₄O, C, 56.41; H, 3.94; N,14.62. found: C, 56.36; H, 4.09; N, 14.27.

EXAMPLE 535-(3-Bromo-phenyl)-7-pyridin-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: m.p. 52-56°C.; ¹H-NMR (CDCl₃) δ 8.52 (d, J=4.8, 1H), 7.66-7.61 (m, 1H), 7.50-7.49(m, 2H), 7.33 (s, 1H), 7.24-7.18 (m, 3H), 7.09-7.07 (m, 1H), 7.01 (s,1H), 5.92 (s, 1H), 4.85(d, J=15.0, 1H), 4.76-4.69 (m, 3H); ¹³C-NMR(CDCl₃) δ 165.8, 156.5, 150.6, 139.0, 138.2, 136.0, 133.3, 131.8, 130.3,126.0, 125.1, 124.4, 124.0, 123.5, 123.3, 61.7, 53.7, 44.1; MS (m/z)382.7 (M+1, 100%); calculated for C₁₈H₁₅BrN₄O, C, 56.41; H, 3.94; N,14.62. found C, 56.76; H, 3.86; N, 14.29.

EXAMPLE 545-(3-Bromo-phenyl)-7-pyridin-4-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: m.p. 50-54°C.; ¹H-NMR (CDCl₃) δ 8.55 (d, J=4.5, 1H), 8.54 (d, J=4.5, 1H), 7.53 (s,1H), 7.51 (s, 1H), 7.33-7.19 (m, 2H), 7.06-7.04 (m, 4H), 4.29 (s, 1H),4.78 (d, J=15.3, 1H), 4.62 (d, J=15.3, 1H), 4.51 (d, J=15.6, 1H), 4.44(d, J=15.6, 1H); ¹³C-NMR (CDCl₃) 8165.1, 150.4, 144.3, 137.4, 135.2,132.4, 130.8, 128.9, 124.5, 124.3, 123.5, 122.4, 121.6, 60.6, 49.8,42.3; MS (m/z) 382.7 (M+1, 100%); calculated for CO₈H₁₅BrN₄O, C, 56.41;H, 3.94; N, 14.62. found C, 56.69; H, 4.29; N, 14.32.

EXAMPLE 555-(3-Bromo-phenyl)-7-cyclohexylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18: ¹H-NMR(DMSO-d₆) δ 7.65 (s, 1H), 7.57 (d, J=9.0, 1H), 7.35 (app. t, J=7.9, 1H),7.29 (s, 1H), 7.03 (d, J=7.8, 1H), 6.94 (s, 1H), 6.18 (s, 1H), 4.65 (d,J=16.1, 1H), 4.55 (d, J=16.2, 1H), 3.27 (d, J=7.3, 2H), 1.69-1.40 (m,6H), 1.20-1.09 (m, 3H), 0.90-0.83 (m, 2H); ¹³C-NMR (DMSO-d₆) 5164.3,139.5, 134.8, 131.2, 131.1, 129.0, 124.9, 122.7, 122.5, 121.9, 59.4,52.3, 42.2, 35.0, 30.1, 29.8, 25.8, 25.1; MS (m/z) 388.1 (M+1, 100%);calculated for C₁₉H₂₂BrN₃O, C, 58.77; H, 5.71; N, 10.82. found: C,58.58; H, 5.96; N, 10.39.

EXAMPLE 564-[5-(3-Bromo-phenyl)-6-oxo-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-ylmethyl]-piperidine-1-carboxylicacid t-butyl ester

The title compound is prepared analogously to Example 18: ¹H-NMR (CDCl₃)δ 7.74 (s, 1H), 7.63 (d, J=9.1, 1H), 7.40-7.33 (m, 2H), 7.24 (s, 1H),7.16 (d, J=9.0, 1H), 6.04 (s, 1H), 4.65 (m, 2H), 4.20 (m, 2H), 3.65-3.20(m, 2H), 2.90-2.68 (m, 2H), 2.32-1.90 (m, 3H), 1.58 (s, 9H), 1.45-1.15(m, 2H); ¹³C-NMR (CDCl₃) 5164.2, 154.0, 136.6, 134.3, 131.6, 130.0,128.1, 123.7, 122.8, 122.7, 121.8, 78.9, 60.0, 52.7, 44.3, 42.6, 35.7,33.9, 29.0, 28.8, 27.7; MS (m/z) 489.2 (M+1, 100%); calculated forC₂₃H₂₉BrN₄O₃, C, 56.44; H, 5.97; N, 11.45. found C, 56.19; H, 6.38; N,11.07.

EXAMPLE 575-(3-Bromo-phenyl)-7-piperidin-4-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onedihydrochloride

The title compound is prepared analogously to Example 18: ¹H-NMR(DMSO-d₆) δ 9.07 (s, 1H), 7.73 (s, 1H), 7.65 (d, J=8.0, 1H), 7.56 (s,1H), 7.43-7.38 (m, 1H), 7.25 (d, J=8.0, 1H), 6.38 (s, 1H), 5.76 (s, 2H),4.82 (s, 2H), 3.50-1.20 (m, 9H); ¹³C-NMR (DMSO-d₆) δ 163.0, 137.2,133.9, 132.1, 131.3, 130.2, 126.0, 124.8, 122.1, 115.3, 60.4, 54.9,51.1, 33.6, 31.3, 26.1, 25.7, 22.5; MS (m/z) 388.9 (M+1, 60%);calculated for C₁₈H₂₁BrN₄O.2HCl, C, 46.77; H, 5.02; N, 12.12. found C,46.54; H, 5.00; N, 12.01.

EXAMPLE 58(+)-5-(3-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18. The product isobtained as a 3:2 mixture of diastereomers with the more polardiastereoisomer predominating. The diastereomers may be separated usingchromatoraphy on silica.

Diastereomer 1 (less polar): m.p. 45-50° C.; [a]D+25.7 (c 1.01, MeOH);¹H-NMR (DMSO-d₆) δ7.69 (1H, s), 7.60 (1H, d, J=7.9), 7.34 (7H, m), 7.10(1H, d, J=8.0), 6.85 (1H, s), 6.30 (1H, s), 5.82 (1H, q, J=7.2), 4.49(1H, d, J=16.2), 4.27 (1H, d, 16.2), 1.49 (3H, d, J=7.2); ¹³C-NMR(DMSO-d₆) δ 164.7, 139.8 (d, J 3.6), 135.3, 131.7(d, J 9.5), 129.5,129.0, 127.9, 127.2 125.4, 123.4, 122.6(d, J 16.7), 60.0, 51.4, 36.8,16.1; e/z (ES) 396/398 (M+1, 100%); calculated for C₂₀H₁₆BrN₃O 0.4H₂O,C, 59.53; H, 4.70; N, 10.41. found C, 59.67; H, 4.68; N, 10.14.

Hydrochloride salt of diastereoisomer 2 (more polar): m.p. 199-202° C.;[α]_(D)+150.0 (c 1.01, MeOH); ¹H-NMR (DMSO-d₆) δ 9.09 (1H, s), 7.67 (1H,d, J=7.9), 7.60 (1H, s), 7.53 (1H, s), 7.34 (7H, m), 6.46 (1H, s), 5.85(1H, q, J=7.1), 4.77 (1H, d, J=16.5), 4.03 (1H, d, J=16.5), 1.57 (3H, d,J=7.1); ¹³C-NMR (DMSO-d₆) δ 163.2, 139.1, 137.1, 134.3, 132.6, 131.7,130.6, 129.0, 128.2, 127.4, 126.6, 125.5, 122.6, 115.9, 61.1, 51.7,36.4, 15.6; e/z (ES) 396 (M+1, 100%); calculated for C₂₀H₁₈N₃OBr HCl, C,55.51; H, 4.43; N, 9.71. found C, 55.21; H, 4.51; N, 9.57.

EXAMPLE 59(−)-5-(3-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18. The product isobtained as a 3:2 mixture of diastereomers with the more polardiastereoisomer predominating. The diastereomers may be separated usingchromatoraphy on silica.

Diastereomer 1 (less polar): m.p. 55-70° C.; [α]_(D)−24.8 (c 0.533,MeOH); ¹H-NMR (DMSO-d₆) δ 7.69 (1H, s), 7.60 (1H, d, J=7.9), 7.34 (7H,m), 7.10 (1H, d, J=8.0), 6.85 (1H, s), 6.30 (1H, s), 5.82 (1H, q,J=7.2), 4.49 (1H, d, J=16.2), 4.27 (1H, d, 16.2), 1.49 (3H, d, J=7.2);¹³C-NMR (DMSO-d₆) 5164.7, 139.8 (d, J 3.6), 135.3, 131.7(d, J 9.5),129.5, 129.0, 127.9, 127.2 125.4, 123.4, 122.6(d, J 16.7), 60.0, 51.4,36.8, 16.1; e/z (ES) 396/398 (M+1, 100%); calculated for C₂₀H₁₈BrN₃O, C,60.62; H, 4.58; N, 10.60. found C, 60.52; H, 4.57; N, 10.27.

Diastereoisomer 2 (more polar): m.p. 199-202° C.; [α]_(D)−156.3 (c1.121, MeOH); ¹H-NMR (DMSO-d₆) δ 7.63 (1H, s), 7.58 (1H, d, J=7.6),7.26-7.37 (5H, m), 7.19 (2H, d, J=7.6), 7.02 (1H, d, J=7.9), 6.90 (1H,s), 6.26 (1H, s), 5.85 (1H, q, J=7.2), 4.65 (1H, d, J=15.8), 3.80 (1H,d, J=15.8), 1.54 (3H, d, J=7.2); ¹³C-NMR (DMSO-d₆) δ 164.80, 139.58,139.51, 135.21, 131.78, 131.58, 129.50, 128.92, 128.02, 127.29, 125.57,123.60, 122.95, 122.39, 60.05, 51.28, 36.80, 15.56; e/z (ES) 396/398(M+1, 100%); calculated for C₂₀H₁₈BrN₃O, C, 60.62; H, 4.58; N, 10.60.found C, 60.39; H, 4.61; N, 10.47.

EXAMPLE 60(+)-5-(4-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18. The product isobtained as a 3:1 mixture of diastereomers with the more polardiastereoisomer predominating. The diastereomers may be separated usingchromatoraphy on silica.

Diastereomer 1 (less polar): m.p. 130-135° C.; ¹H-NMR (DMSO-d₆) δ7.67(1H, s), 7.62 (2H, d, J=8.43), 7.3 (5H, m), 7.1 (2H, d, J=8.43),6.84 (1H, s), 6.27 (1H, s), 5.82 (1H, q, J=7.1), 4.45 (1H, d, J=15.9),4.25 (1H, d, J=15.9), 1.48 (3H, d, J=7.18); ¹³C-NMR (DMSO-d₆) δ 164.39,139.38, 136.12, 134.85, 131.89, 128.51, 128.24, 127.47, 126.73, 122.93,122.31, 121.69, 59.65, 50.83, 36.28, 15.61; e/z (ES) 396/398 (M+1,100%).

Diastereomer 2 (more polar): m.p. 147-148° C.; [a]D+179.4 (c 0.93,MeOH); ¹H-NMR (DMSO-d₆) δ 7.6 (1H, s), 7.58(2H, d, J=8.3), 7.28 (3H, m),7.17 (2H, m), 7.01 (2H, d, J=8.3), 6.89 (1H, s), 6.23 (1H, s), 5.83 (1H,q, J=7.0), 4.62 (1H, d, J=15.9), 3.79 (1H, d, J=15.9), 1.54 (3H, d,J=7.1); ¹³C-NMR (DMSO-d₆) 8164.49, 139.03 135.90, 134.73, 131.79,128.46, 128.35, 127.53, 126.85, 123.04, 122.65, 121.65, 59.79, 50.77,36.32, 15.13; e/z (ES) 396/398 (M+1, 100%); calculated for C₂₀H₁₈BrN₃O,C, 60.62; H, 4.58; N, 10.60. found C, 60.68; H, 4.52; N, 10.62.

EXAMPLE 61(−)-5-(4-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 18. The product isobtained as a 3:1 mixture of diastereomers with the more polardiastereoisomer predominating. The diastereomers may be separated usingchromatoraphy on silica.

Diastereoisomer 1 (less polar): m.p. 167-168° C.; [α]_(D)−16.1 (c 0.29,MeOH); ¹H-NMR (DMSO-d₆) δ 7.67 (1H, s), 7.62 (2H, d, J=8.4), 7.32 (5H,m), 7.10 (2H, d, J=8.4), 6.84 (1H, s), 5.82 (1H, q, J=7.1), 4.45 (1H, d,J=15.9), 4.26 (1H, d, J=15.9), 1.48 (3H, d, J=7.1); ¹³C-NMR (DMSO-d₆) δ164.4, 139.4, 136.1, 134.9, 131.9, 128.5, 128.3, 127.5, 126.7, 122.9,122.3, 121.7, 59.7, 50.8, 36.3, 15.6; e/z (ES) 394/396 (M+1, 100%);calculated for C₂₀H₁₈N₃OBr, C, 60.62; H, 4.58; N, 10.60. found C, 60.55;H, 4.61; N, 10.61.

Diastereoisomer 2 (more polar): m.p. 146-147° C.; [α]_(D)−173.8 (c 0.92,MeOH); ¹H-NMR (DMSO-d₆) δ 7.60 (1H, s), 7.58 (2H, d, J=8.3), 7.29 (4H,m), 7.16 (2H, m), 7.02 (2H, d, J=8.3), 6.90 (1H, s), 6.23 (1H, s), 5.83(1H, q, J=7.0), 4.62 (1H, d, J=15.9), 3.80 (1H, d, J=15.9), 1.54 (3H, d,J=7.0); ¹³C-NMR (DMSO-dr) δ 164.5, 139.0, 135.9, 134.7, 131.8, 128.5,128.4, 127.5, 126.9, 123.0, 122.6, 121.7, 59.8, 50.8, 36.3, 15.1; e/z(ES) 394/396 (M+1, 100%); calculated for C₂₀H₁₈N₃OBr, C, 60.62; H, 4.58;N, 10.60. found C, 60.28; H, 4.70; N, 10.61.

EXAMPLE 62(−)-(4-[6-Oxo-7-((S)-1-phenyl-ethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile

The title compound is prepared analogously to Example 18. The product isobtained as a mixture of diastereomers. The diastereomers may beseparated using chromatoraphy on silica.

Diastereomer 1 (less polar): m.p. 157-158°° C.; [α]_(D)−13.8 (c 0.94,MeOH); ¹H NMR (DMSO-d₆) δ 7.90 (d, J=8.4, 2H), 7.68 (s, 1H), 7.39-7.26(m, 7H), 6.86 (s, 1H), 6.41 (s, 1H), 5.80 (q, J=7.2, 1H), 4.48 (d,J=15.9, 1H), 4.27 (d, J=15.9, 1H), 1.47 (d, J=7.2, 3H); ¹³C-NMR(DMSO-d₆) δ 163.9, 141.8, 139.3, 134.9, 133.0, 128.5, 127.5, 127.1,126.7, 123.0, 122.3, 118.3, 111.3, 59.9, 51.0, 36.3, 15.6; MS (m/z)343.1 (M+1, 100%); calculated for C₂₁H₁₈N₄O, C, 73.67; H, 5.30; N,16.36. found C, 73.48; H, 5.24; N, 16.31.

Diastereomer 2 (more polar): m.p. 75-77° C.; [α]_(D)−213.0 (c 1.00,MeOH); ¹H NMR (DMSO-d₆) δ 7.87 (d, J=8.3, 2H), 7.60 (s, 1H), 7.31-7.24(m, 5H), 7.14 (d, J=6.9, 2H), 6.92 (s, 1H), 6.37 (s, 1H), 5.81 (q,J=7.1, 1H), 4.63 (d, J=16.0, 1H), 3.81 (d, J=16.0, 1H), 1.54 (d, J=7.1,3H); ¹³C-NMR (DMSO-d₈) δ 166.1, 143.8, 141.1, 136.9, 135.0, 130.6,129.7, 129.3, 128.9, 125.3, 124.8, 120.4, 113.4, 62.2, 53.0, 38.5, 17.2;MS (m/z) 343.1 (M+1, 100%); calculated for C₂₁H₁₈N₄O.0.1H₂O, C, 73.06;H, 5.28; N, 16.24. found C, 72.84; H, 5.46; N, 16.01.

EXAMPLE 63 7-Benzyl-7,8-dihydro-imidazol-[1,5-a]pyrazin-6-onehydrochloride

A. Ethyl (5-hydroxy-imidazoyl-1-yl)-acetate

To a solution of the title A compound in Example 18,4-(t-butyldimethylsilanoxy-methyl)-1-trityl-1H-imidazole (18.16 g, 40.0mmol) in acetonitrile (50 mL) is added ethyl bromoacetate (6.68 g, 40.0mmol) and the mixture stirred for 18 h. The mixture is vacuum filtered,the filtrate is concentrated in vacuo and treated with EtOH/HCl (g)solution (35 mL) and the mixture is stirred for 4 days. The resultingsuspension is vacuum filtered and washed with fresh EtOH to give a clearfiltrate. The solution is concentrated to a smaller volume and treatedwith propylene oxide (25 mL) and stirred overnight at RT. Again vacuumfiltered off the solids and concentrated the filtrate in vacuo. Theresidue is chromatographed through a silica gel column and eluted withEtOAc:MeOH:NH₄OH (95:5:1) to give ethyl(5-hydroxy-imidazoyl-1-yl)-acetate as an oil: ¹H-NMR (CDCl₃) δ7.45 (1H,s), 6.90 (1H, s), 4.80 (2H, s), 4.59 (2H, s), 4.23 (2H, q, J=7.2), 3.73(1H, br s), 1.29 (3H, t, J=7.2); ¹³C-NMR (CDCl3) δ 166.2, 137.3, 129.4,126.2, 60.3, 52.3, 44.5, 12.2; e/z (ES) 185 (M+1, 100%).

B. Ethyl (5-formyl-imidazoyl-1-yl)-acetate

The title B compound is prepared analogously to the title C compound inExample 18: ¹H-NMR (CDCl₃) δ 9.75 (1H, s), 7.84 (1H, s), 7.69 (1H, s),5.05 (2H, s), 4.25 (2H, q, J=7.2), 1.29 (3H, t, J=7.2); ¹³C-NMR (CDCl₃)δ 179.9, 167.4, 143.5, 131.6, 62.5, 48.4, 14.4; e/z (ES) 183 (M+1,100%).

C. 7-Benzyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one hydrochloride

The title C compound is prepared analogously to the title D compound inExample 18: m.p. 201-204° C.; ¹H-NMR (DMSO-d₈) δ 9.12 (1H, s), 7.56 (1H,s), 7.35 (5H, m), 5.04 (2H, s), 4.71 (2H, s), 4.59 (2H, s); ¹³C-NMR(DMSO-d₆) δ 162.8, 136.3, 133.6, 129.0, 128.2, 127.9, 125.4, 114.6,49.4, 47.9, 41.3; e/z (ES) 228 (M+1, 100%); calculated for C₁₃H₁₃N₃OHCl, C, 59.21; H, 5.35; N, 15.93. found C, 58.87; H, 5.41; N, 15.85.

EXAMPLE 64 7-(4-Methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 63: m.p. 105-108°C.; ¹H-NMR (DMSO-d₆) δ 7.60 (s, 1H), 7.19-7.13 (m, 4H), 6.75 (s, 1H),4.81 (s, 2H), 4.61 (s, 2H), 4.46 (s, 2H), 2.28 (s, 3H); ¹³C-NMR(DMSO-d₆) δ 164.0, 136.5, 134.5, 133.3, 129.0, 127.7, 122.3, 122.2,48.6, 46.2, 41.5, 20.6; MS (m/z) 242.1 (M+1, 100%); calculated forC₁₄H₁₅N₃O.0.1H₂O, C, 69.11; H, 6.17; N, 17.28. found C. 68.95; H, 6.39;N, 17.07.

EXAMPLE 65 7-(4-Fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 63: m.p. 112-114°C.; ¹H-NMR (DMSO-d₆) δ 7.60 (s, 1H), 7.37-7.32 (m, 2H), 7.20-7.14 (m,2H), 6.76 (s, 1H), 4.81 (s, 2H), 4.64 (s, 2H), 4.49 (s, 2H); ¹³C-NMR(DMSO-d₆) δ 164.2, 161.4 (d, J=241.5), 134.5, 132.7 (d, J=3.0), 129.8(d, J=8.2), 122.3, 122.1, 115.2 (d, J=21.0), 48.3, 46.2, 41.7; MS (m/z)246.0 (M+1, 100%); calculated for C₁₃H₁₂FN₃O, C, 63.66; H, 4.93; N,17.13. found C, 63.43; H, 4.97; N, 17.00.

EXAMPLE 663-(7-Benzyl-5-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

To a solution of the title compound of Example 33,7-benzyl-5-(3-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one(0.550 g, 1.44 mmol) in DMF (2 mL) is added zinc(II) cyanide (0.100 g,0.85 mmol) followed by tetrakistriphenylposphine palladium (0) (0.100 g,6 mol %). The reaction mixture is degassed, purged with nitrogen thenheated at 90° C. for 1 h. The reaction mixture is partitioned betweenaqueous ammonium hydroxide (2N) and EtOAc. Following washing of thecombined organic phases with brine, drying (anhydrous sodium sulfate)and removal of the solvent the residue is subjected to flashchromatography (silica) eluting with EtOAc:MeOH:NH₄OH (90:10:1) to givethe desired material which is recrystallized from diethyl ether toafford3-(7-benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile:m.p. 163-165° C.; ¹H-NMR (CDCl₃) δ 7.66 (1H, d, J=7.6), 7.50 (1H, t,J=6.8), 7.48 (1H, s), 7.33 (2H, m), 7.31 (3H, m), 7.17 (2H, m), 7.01(1H, s), 6.01 (1H, s), 4.78 (1H, d, J=14.7), 4.60 (1H, d, J=14.7), 4.50(1H, d, J=15.7), 4.41 (1H, d, J=15.7); ¹³C-NMR (CDCl₃) 8164.1, 137.4,135.0, 134.8, 132.6, 130.4, 130.0, 129.4, 129.0, 128.2, 128.0, 124.3,121.8, 117.9, 113.5, 60.3, 50.7, 41.5; e/z (ES) 329 (M+1, 100%);calculated for C₂₀H₁₆N₄O, C, 73.15; H, 4.91; N, 17.06. found C, 72.81;H, 4.95; N, 16.90.

EXAMPLE 673-[7-(4-Methyl-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 260-263°C.; ¹H-NMR (DMSO-d₆) δ 9.11 (1H, s), 7.94 (1H, d, J=6.8), 7.81 (1H, s),7.67 (3H, m), 7.16 (4H, s), 6.52 (1H, s), 4.74 (1H, d, J=14.7), 4.72(2H, s), 4.58 (1H, d, J=14.7), 2.28 (3H, s); ¹³C-NMR (DMSO-d₆) δ 162.9,137.4, 136.6, 134.3, 133.5, 133.0, 132.9, 131.5, 130.7, 129.6, 128.3,125.2, 118.6, 115.6, 112.5, 60.8, 49.7, 41.0, 21.0; e/z (ES) 342 (M+1,100%); calculated for C₂₁H₁₈N₄O HCl, C, 66.57; H, 5.05; N, 14.79. foundC, 66.23; H, 4.94; N, 14.43.

EXAMPLE 683-[7-(4-Fluoro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 260-263°C.; ¹H-NMR (DMSO-d₆) δ 9.08 (1H, s), 7.94 (1H, d, J=6.8), 7.82 (1H, s),7.67 (3H, m), 7.35 (1H, d, J=8.7), 7.33 (1H, d, J=8.7), 7.16 (2H, app t,J=8.7), 6.51 (1H, s), 4.80 (1H, d, J=15.0), 4.79 (1H, d, J=16.9), 4.72(1H, d, J=16.9), 4.59 (1H, d, J=15.0); ¹³C-NMR (DMSO-d₆) δ 163.1, 162.0(d, J=243.4), 136.6, 134.4, 133.5, 133.0, 132.4 (d, J=2.9), 131.6,130.7, 130.4 (d, J=8.0), 125.1, 118.6, 115.8 (d, J=21.8), 115.7, 112.5,60.8, 49.6, 41.2; e/z (ES) 347 (M+1, 100%); calculated for C₂₀H₁₅N₄° F.HCl, C, 62.75; H, 4.21; N, 14.64. found C, 62.40; H, 3.86; N, 14.28.

EXAMPLE 693-[7-(4-Chloro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 236-238°C.; ¹H-NMR (DMSO-d₆) δ 9.08 (1H, s), 7.94 (1H, d, J=7.2), 7.83 (1H, s),7.69 (3H, m), 7.42 (2H, d, J=8.7), 7.32 (2H, d, J=8.7), 6.52 (1H, s),4.81 (1H, d, J=15.1), 4.79 (1H, d, J=16.2), 4.73 (1H, d, J=16.2), 4.59(1H, d, J=15.1); ¹³C-NMR (DMSO-d₆) δ 163.2, 136.6, 135.2, 134.4, 133.5,133.0, 132.7, 131.6, 130.7, 130.2, 129.0, 125.1, 118.6, 115.7, 112.5,60.8, 49.4, 41.3; e/z (ES) 363 (M+1, 100); calculated for C₂₀H₁₅N₄O HCl0.2H₂O, C, 59.62; H, 3.85; N, 13.91. found C, 59.69; H, 3.97; N, 13.83.

EXAMPLE 703-[7-(4-Methoxy-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 246-248°C.; ¹H-NMR (DMSO-d₆) δ 9.08 (1H, s), 7.94 (1H, d, J=6.8), 7.80 (1H, s),7.69 (3H, m), 7.22 (2H, d, J=8.2), 6.91 (2H, d, J=8.2), 6.51 (1H, s),4.73 (1H, d, J=14.7), 4.71 (2H, s), 4.55 (1H, d, J=14.7), 3.74 (3H, s);¹³C-NMR (DMSO-d₆) 8162.9, 159.2, 136.7, 134.3, 133.4, 132.9, 131.5,130.7, 129.8, 127.9, 125.1, 118.6, 115.7, 114.4, 112.5, 60.7, 55.4,49.4, 40.9; e/z (ES) 359 (M+1, 100%); calculated for C₂₁H₁₈N₄O₂, C,63.88; H, 4.85; N, 14.19. found C, 63.61; H, 4.73; N, 13.95.

EXAMPLE 713-[7-(4-Fluoro-phenethyl)-6-oxo-5,6,7,8-tetrahydro-imidazol-1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 221-223°C.; ¹H-NMR (DMSO-d₆) δ 9.05 (1H, s), 7.92 (1H, d, J=7.9), 7.72 (1H, s),7.66 (2H, m), 7.51 (1H, d, J=8.3), 7.18 (2H, dd, J=8.7, 5.7), 6.99 (2H,m), 6.40 (1H, s), 4.81 (1H, d, J=16.6), 4.70 (1H, d, J=16.6), 3.86 (1H,m), 3.58 (1H, m), 2.84 (2H, m); ¹³C-NMR (DMSO-d₆) δ 162.2, 160.6 (d,J=243.0), 136.0, 134.2, 133.9, 132.9, 132.0, 130.7, 130.3 (d, J=7.6),130.2, 124.8, 118.1, 115.2, 114.9 (d, J=21.3), 112.0, 60.26, 48.0,41.06, 31.2; e/z (ES) 361 (M+1, 100%); calculated for C₂₁H₁₇N₄° F. HCl,C, 63.56; H, 4.57; N, 14.12. found C, 63.28; H, 4.44; N, 14.01.

EXAMPLE 723-[7-Phenethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 203-205°C.; ¹H-NMR (DMSO-d₆) δ 9.07 (1H, s), 7.92 (1H, d, J=7.5), 7.70 (1H, s),7.66 (2H, m), 7.52 (1H, d, J=8.3), 7.18 (5H, m), 6.42 (1H, s), 4.80 (1H,d, J=16.6), 4.67 (1H, d, J=16.6), 3.86 (1H, m), 3.60 (1H, m), 2.85 (2H,m); ¹³C-NMR (DMSO-d₆) 8162.6, 138.6, 136.5, 134.4, 133.3, 132.5, 131.2,130.7, 129.0, 128.7, 126.7, 125.2, 118.6, 115.6, 112.5, 60.7, 48.6,41.6, 32.6; e/z (ES) 343 (M+1, 100%); calculated for C₂₁H₁₈N₄O HCl, C,66.57; H, 5.05; N, 14.79. found C, 66.27; H, 4.91; N, 14.62.

EXAMPLE 733-[7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrilehydrochloride

The title compound is prepared analogously to Example 66: m.p. 225-227°C.; ¹H-NMR (DMSO-d₆) δ 9.12 (1H, s), 7.92 (1H, m), 7.83 (1H, s), 7.75(1H, s), 7.67 (2H, m), 6.47 (1H, s), 4.94 (1H, d, J=16.9), 4.91 (1H, d,J=16.9), 3.39 (2H, d, J=7.2), 1.05(1H, m), 0.48 (2H, m), 0.28 (2H, m);¹³C-NMR (DMSO-d₆) δ 161.9, 136.0, 133.5, 132.6, 132.0, 130.8, 130.0,124.6, 117.8, 114.8, 111.8, 59.9, 50.4, 40.6, 8.3, 2.8, 2.7; e/z (ES)293 (M+1, 100%); calculated for C₁₇H₁₆N₄O HCl, C, 62.10; H, 5.21; N,17.04. found C, 62.02; H, 5.05; N, 17.11.

EXAMPLE 745-(4′-Chlorobiphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

To a solution of the title compound of Example 21,5-(4-bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one(0.125 g, 0.30 mmol) in DMF (2 mL) is added potassium phosphate (0.129g, 0.61 mmol) and 4-chlorophenyl boronic acid (0.057 g, 0.36 mmol)followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.025 g, 10 mol %). The reaction mixture is degassed, purged withnitrogen then heated at 95° C. for 5 h. The reaction mixture ispartitioned between water and EtOAc. The combined organic phases arewashed with brine, dried (anhydrous sodium sulfate) and concentrated.The residue is subjected to flash chromatography (silica) eluting withEtOAc: MeOH:NH₄OH (90:10:1) to give5-(4′-chlorobiphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onewhich is dissolved in diethyl ether and treated with HCl(g)-MeOH and theprecipitated product,5-(4′-chlorobiphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride is collected by filtration and dried: m.p. 270-273° C.;¹H-NMR (DMSO-d₈) δ 9.19 (1H, s), 7.73 (5H, m), 7.54 (2H, d, J=8.3), 7.37(2H, d, J=8.3), 7.22 (2H, d, J=8.6), 6.90 (2H, d, J=8.6), 6.49 (1H, s),4.67 (4H, m), 3.73 (3H, s); ¹³C-NMR (DMSO-d₆) 163.0, 158.8, 139.6,137.9, 134.4, 133.9, 132.7, 129.4, 128.9, 128.5, 127.6, 127.4, 124.7,115.3, 114.0, 60.8, 55.0, 48.9; e/z (ES) 444 (M+1, 100%); calculated forC₂₆H₂₂N₃O₂Cl HCl, C, 65.01; H, 4.83; N, 8.75. found C, 64.64; H, 4.78;N, 8.74.

EXAMPLE 757-(4-Methoxy-benzyl)-5-(4-thiophen3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 74: m.p. 162-164°C.; ¹H-NMR (DMSO-d₆) δ 7.89 (1H, dd, J=2.8, 1.1), 7.72 (2H, d, J=8.3),7.65 (2H, m), 7.54 (1H, dd, J=5.0, 1.1), 7.15 (4H, app t, J=9.0), 6.90(1H, s), 6.87 (2H, d, J=8.6), 6.25 (1H, s), 4.55 (4H, m), 3.71 (3H, s);¹³C-NMR (DMSO-d₆) δ 165.2, 159.1, 141.0, 136.2, 135.6, 135.2, 129.6,128.6, 127.6, 127.1, 127.0, 126.5, 123.3, 122.7, 121.9, 114.4, 60.3,55.4, 49.2, 41.5; e/z (ES) 416 (M+1, 100%); calculated for C₂₄H₂₁N₃O₂S,C, 69.37; H, 5.09; N, 10.11. found C, 69.19; H, 5.08; N, 9.91.

EXAMPLE 767-Cyclopropylmethyl-5-(4-thiophen-3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 74: m.p. 217-219°C.; ¹H-NMR (DMSO-d₆) δ 9.22 (1H, s), 7.94 (1H, dd, J 2.9, 1.2), 7.78(2H, d, J 8.3), 7.75 (1H, s), 7.67 (1H, m), 7.57 (1H, dd, J 5.0, 1.3),7.33 (2H, d, J 8.3), 6.39(1H, s), 4.97(1H, d, J 16.7), 4.84 (1H, d, J16.7), 3.50 (1H, dd, J 13.8, 7.0), 3.32 (1H, dd, J 13.8, 7.0), 1.03 (1H,m), 0.48 (2H, m), 0.28 (2H, m); ¹³C-NMR (DMSO-d₆) δ 163.3, 162.7, 140.8,136.3, 134.2, 134.0, 127.9, 127.7, 127.2, 126.5, 125.4, 122.2, 115.6,61.2, 51.0, 41.3, 9.1, 3.7, 3.4; e/z (ES) 350 (M+1, 100%); calculatedfor C₂₀H₁₉N₃OS HCl, C, 62.25; H, 5.22; N, 10.89. found C, 61.89; H,5.26; N, 10.73.

EXAMPLE 777-Benzyl-5-(4′-fluoro-biphenyl-3-yl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 74: m.p. 235-237°C.; ¹H-NMR (DMSO-d₆) δ 9.16 (1H, s), 7.68 (4H, m), 7.54 (2H, m), 7.30(8H, m), 6.49 (1H, s) 4.75 (4H, m); ¹³C-NMR (DMSO-d₆) δ 163.61, 162.75,160.85, 140.46, 136.20, 134.40, 130.32, 129.30, 129.20, 129.05, 128.22,128.08, 127.95, 126.33, 125.86, 124.98, 116.33, 116.04, 115.89, 61.45,50.00, 41.28; e/z (ES) 398 (M+1, 100%); calculated for C₂₅H₂₀FN₃O HCl0.2H₂O, C, 68.63; H, 4.93; N, 9.60. found C, 68.35; H, 4.73; N, 9.66.

EXAMPLES 785-Biphenyl-4-yl-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 74: m.p. 189-190°C.; e/z (ES) 398 (M+1, 100%).

EXAMPLE 797-Benzyl-5-biphenyl-3-yl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 74: m.p. 232-234°C.; e/z (ES) 380 (M+1, 100%).

EXAMPLE 80 Methyl4-(7-benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzoatehydrochloride

To a solution of the title compound of Example 23,7-benzyl-5-(4-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one(0.202 g, 0.53 mmol) in DMSO:MeOH (2 mL; 5:1) are added triethylamine(0.147 mL, 1.06 mmol), diphenylposhinopropane (0.044 g, 20 mol %), andpalladium (II) acetate (0.024 g, 20 mol %). The reaction mixture isdegassed, purged with carbon monoxide and then heated at 70° C. for 16h. The reaction mixture is cooled, then partitioned between water andEtOAc. Following washing of the combined organic phases with brine,drying (anhydrous sodium sulfate) the residue is subjected to flashchromatography (silica) eluting with EtOAc:MeOH:NH₄OH (90:10:1) to givethe desired free base as an oil, which is dissolved in methanol and HCl(g) in diethyl ether is added to afford methyl4-(7-benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzoatehydrochloride: m.p. 236-238° C.; ¹H-NMR (DMSO-d₈) δ 9.16 (1H, s), 8.01(2H, d, J=8.4), 7.71 (1H, s), 7.44 (2H, d, 8.4), 7.33 (3H, m), 7.23 (2H,m), 6.58 (1H, s), 4.70 (4H, m), 3.87 (3H, s); ¹³C-NMR (DMSO-d₆) δ 166.0,163.2, 139.9, 136.1, 134.5, 130.6, 130.3, 129.0, 128.1, 127.8, 125.2,115.8, 61.4, 52.7, 49.9, 41.1; e/z (ES) 362 (M+1, 100%); calculated forC₂₁H₁₉N₃O₃ HCl 0.2H₂O, C, 62.82; H, 5.06; N, 10.50. found C, 62.82; H,5.06; N, 10.47.

EXAMPLE 814-7-Benzyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride

To a solution of the title compound of Example 3,4-(7-benzyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile(0.24 g, 0.63 mmol) in 5 mL of THF at −78° C. is added LHMDS (0.70 mL,0.70 mmol) and the resulting solution is stirred for 15 min. To thissolution is added methyl iodide (0.040 mL, 0.67 mmol) and the solutionis stirred for 15 min, then warmed gradually to RT. The reaction mixtureis quenched by addition of NH₄Cl and extracted with EtOAc. The organicsolution is washed with brine, dried (anhydrous sodium sulfate) andevaporated to an oil. Purification by flash chromatography (silica gel)eluting with EtOAc:MeOH:NH₄OH (95:5:0.5) gives the free base which isdissolved in acetone and HCl (g) in diethyl ether is added to afford4-(7-benzyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrilehydrochloride: m.p. 230-232° C.; ¹H-NMR (DMSO-d₆) δ 9.54 (1H, s), 7.90(2H, d, J=8.7), 7.74 (1H, s), 7.32 (3H, m), 7.22 (2H, d, J=8.7), 7.15(2H, m), 4.73 (1H, d, J=16.9), 4.71 (1H, d, J=14.6), 4.66 (1H, d,J=14.6), 4.12 (1H, d, J=16.9), 2.25 (3H, s); ¹³C-NMR (DMSO-d₆) δ 163.1,141.1, 133.8, 132.3, 131.3, 126.8, 125.8, 125.7, 124.0, 123.7, 116.2,114.2, 110.0, 64.6, 48.4, 38.5, 22.6; e/z (ES) 343 (M+1, 100%);calculated for C₂₁H₁₈N₄O HCl, C, 66.58; H, 5.05; N, 14.79. found C,66.41; H, 5.01; N, 14.80.

EXAMPLE 825-(4-Bromo-phenyl)-7-cyclopropylmethyl-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 81: m.p. 228-230°C.; ¹H-NMR (DMSO-d₆) δ 9.35 (1H, s), 7.53 (1H, s), 7.39 (2H, d, J=8.4),6.74 (2H, d, J=8.4), 4.63 (1H, d, J=16.5), 3.99 (1H, d, J=16.5), 3.31(1H, dd, J=13.8, 7.0), 2.95 (1H, dd, J=13.8, 7.0), 1.91 (3H, s), 0.71(1H, m), 0.18 (2H, m), 0.0 (2H, m); ¹³C-NMR (DMSO-d₆) δ 165.4, 162.7,137.9, 134.3, 132.6, 127.2, 126.4, 122.6, 116.0, 66.7, 51.6, 25.0, 9.0,3.6, 3.2; e/z (ES) 360/362 (M+1, 100%); calculated for C₁₇H₁₈BrN₃O HCl,C, 51.47; H, 4.83; N, 10.59. found C, 51.15; H, 4.76; N, 10.38.

EXAMPLE 835-(3-Bromo-phenyl)-7-cyclopropylmethyl-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 81: m.p. 234-236°C.; ¹H-NMR (DMSO-d₆) δ 0.20-0.34 (2H, m), 0.41-0.49 (2H, m), 0.92-1.04(1H, m), 2.15 (3H, s), 3.22 (1H, dd, J=13.8, 7.2), 3.55 (1H, dd, J=13.8,7.2), 4.27 (1H, d, J=16.3), 4.86 (1H, d, J=16.3), 7.00 (1H, d, J=8.0),7.27 (1H, s), 7.39 (1H, t, J=8.0), 7.62 (1H, d, J=8.0), 7.74 (1H, s),9.46 (1H, s); ¹³C-NMR (DMSO-d₆) δ 3.26, 3.49, 9.04, 25.05, 40.86, 51.71,66.48, 116.54, 122.88, 124.08, 126.18, 127.81, 131.84, 132.30, 134.45,140.98, 165.40; e/z (ES) 360/362 (M+1, 100%); calculated for C₁₇H₁₈BrN₃OHCl, C, 51.47; H, 4.83; N, 10.59. found C, 51.11; H, 4.87; N, 10.48.

EXAMPLE 845-(4-Bromo-phenyl)-7-(4-fluoro-benzyl)-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-onehydrochloride

The title compound is prepared analogously to Example 81: m.p. 235-237°C.; ¹H-NMR (DMSO-d₆) δ 9.54 (1H, s), 7.73 (1H, s), 7.61 (2H, d, J=8.7),7.25 (2H, dd, J=8.7, 5.7), 7.14 (2H, app t, J=8.9), 6.95 (2H, d, J=8.7),4.72 (1H, d, J=16.6), 4.67 (2H, s), 4.11 (1H, d, J=16.6), 2.2 (3H, s);¹³C-NMR (DMSO-d₆) δ 165.7, 162.0 (d, J=243.0), 137.7, 134.4, 132.5,132.4, 130.3 (d, J=8.3), 127.2, 126.0, 122.7, 116.2, 115.8 (d, J=21.9),66.7, 49.8, 25.0; e/z (ES) 413/415 (M+1, 100%); calculated forC₂₀H₁₇BrFN₃O HCl, C, 53.29; H, 4.02; N, 9.32. found C, 53.39; H, 3.73;N, 9.28.

EXAMPLE 854-[7-(4-Fluoro-benzyl)-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile

The title compound is prepared analogously to Example 81: m.p. 66-70°C.; ¹H-NMR (CDCl₃) δ 7.70 (s, 1H), 7.61 (d, J=8.3, 2H), 7.11-6.94 (m,7H), 4.63 (app. t, J=15.0, 2H), 4.32 (d, J=15.5, 1H), 4.00 (d, J=15.7,1H), 2.22 (s, 3H); ¹³C-NMR (CDCl₃) δ 167.4, 162.9 (d, J=245.2), 145.5,134.2, 133.2, 131.4 (d, J=3.0), 130.0 (d, J=8.3), 125.9, 125.0, 123.7,118.3, 116.3 (d, J=21.0), 113.2, 65.7, 51.0, 41.8, 25.6; MS (m/z) 360.8(M+1, 100%); calculated for C₂₁H₁₇FN₄O.0.2H₂O, C, 69.23; H, 4.78; N,15.38. found: C, 69.16; H, 4.91; N, 15.18.

EXAMPLE 864(7-[(s)-1-(4-Fluoro-phenyl)-ethyl]-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl}-benzonitrile

The title compound is prepared analogously to Example 81. The product isobtained as a mixture of diastereomers. The diastereomers may beseparated using chromatoraphy on silica.

Diastereomer 1 (less polar): m.p. 78-82° C.; [α]_(D)−3.3 (c 1.00, MeOH);¹H-NMR (DMSO-d₆) δ 8.05 (s, 1H), 7.89 (d, J=9.0, 2H), 7.37-7.29 (m, 3H),7.22 (d, J=9.0, 2H), 7.04 (d, J=9.0, 2H), 6.85 (s, 1H), 5.79 (q, J=6.0,1H), 4.20 (d, J=15.0, 1H), 3.88 (d, J=15.0, 1H), 2.13 (s, 3H), 1.38 (d,J=6.0, 3H); ¹³C-NMR (DMSO-d₆) δ 166.9, 145.8, 139.8, 134.9, 133.5,129.0, 127.9, 127.1, 125.8, 123.9, 118.6, 111.6, 65.2, 52.0, 36.5, 25.2,15.9; MS (m/z) 356.8 (M+1, 100%); calculated for C₂₂H₂₀N₄O.0.1H₂O, C,73.69; H, 5.64; N, 15.63. found, C, 73.29; H, 5.92; N, 15.45.

Diastereomer 2 (more polar): m.p. 72-75° C.; [α]_(D)−147.0 (c 1.00,MeOH); ¹H-NMR (DMSO-d₆) δ 8.02 (s, 1H), 7.84 (d, J=9.0, 2H), 7.26-7.23(m, 3H), 7.09-7.07 (m, 2H), 7.00 (s, 1H), 6.96 (d, J=6.0, 2H), 5.82 (q,J=9.0, 1H), 4.53 (d, J=15.0, 1H), 3.23 (d, J=15.0, 1H), 2.12 (s, 3H),1.50 (d, J=9.0, 3H); ¹³C NMR (DMSO-ds) δ 164.6, 143.3, 137.1, 132.6,131.1, 126.6, 125.8, 125.0, 123.7, 122.2, 121.8, 116.4, 109.3, 63.1,49.7, 34.2, 22.7, 13.4; MS (m/z) 357.1 (M+1, 100%); calculated forC₂₂H₂₀N₄O.0.1H₂O, C, 73.69; H, 5.64; N, 15.63. found C, 73.23; H, 5.87;N, 15.12.

EXAMPLE 875-Benzyl-5-(4-bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one

The title compound is prepared analogously to Example 81: m.p. 166-168°C.; ¹H-NMR (DMSO-d₆) δ 7.81 (1H, s), 7.62 (2H, d, J=8.6), 7.14 (7H, m),7.04 (2H, app t, J=7.5), 6.79 (2H, d, J=7.2), 6.73 (1H, s), 4.75 (1H, d,J=14.5), 4.40 (1H, d, 16.1), 4.28 (1H, d, J=14.5), 4.18 (1H, d, J=13.7),3.73 (2H, m); ¹³C-NMR (DMSO-d₆) δ 166.2, 162.0 (d, J=243.8), 141.6,135.4, 135.1, 132.3, 132.0, 130.6 (d, J=8.3), 130.0, 128.6, 128.3,127.4, 122.6, 122.5, 122.0, 115.6 (d, J=21.9), 67.67, 49.7, 43.2, 41.7;e/z (E/S) 489/491 (M+1, 100%); calculated for O₂₆H₂₁BrFN₃O, C, 63.68; H,4.32; N, 8.57. found C, 63.68; H, 4.34; N, 8.45.

EXAMPLE 884-(5,7-Dibenzyl-6-oxo-5,6,7,8-tetrahydro-imidazol[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 81: m.p. 246-248°C.

EXAMPLE 894-(5-Benzyl-7-cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 81: m.p. 156-158°C.

EXAMPLE 905-(4-Bromophenyl)₇-(4-methoxy-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]-pyrazinedihydrochloride

To a solution of the title compound of Example 21,5-(4-bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one(0.471 g, 1.14 mmol) in THF (5 mL) at RT is added borane (6.85 mL, 6.85mmol). The reaction is stirred for 18 h and quenched with MeOH. Thereaction mixture is evaporated to dryness, partitioned between water andEtOAc. The combined organic phases are washed with brine, dried(anhydrous sodium sulfate), concentrated and the residue is subjected toflash chromatography (silica) eluting with EtOAc:MeOH:NH₄OH (90:10:1) togive the desired material. This material is dissolved in diethyl ether,HCl(g)-MeOH is added and the hydrochloride crystallizes to afford6(4-bromophenyl)-7-(4-methoxy-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]-pyrazinedihydrochloride: m.p. 270-273° C.

EXAMPLE 915-(4-Bromophenyl)-7-benzyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazinep-toluene sulfonate

To a solution of the title compound of Example 23,5-(4-bromo-phenyl)-7-benzyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one(0.471 g, 1.14 mmol) in THF (5 mL) at RT is added borane (6.85 mL, 6.85mmol). The reaction is stirred for 18 h and quenched with MeOH. Thereaction mixture is evaporated to dryness, partitioned between water andEtOAc. The combined organic phases are washed with brine, dried(anhydrous sodium sulfate), concentrated and the residue is dissolved inacetone, p-toluene sulfonic acid is added and the desired5-(4-bromophenyl)-7-benzyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazinep-toluenesulfonate crystallizes: m.p. 223-225° C.; ¹H-NMR (DMSO-d₆) δ8.81 (1H, s), 7.63 (2H, d, J=8.7), 7.51 (1H, s), 7.47 (2H, d, J=7.8),7.27 (5H, m), 7.20 (2H, m), 7.11 (2H, d, J=7.8), 5.70 (1H, dd, J=6.4,4.1), 3.85 (1H, d, J=13.3), 3.78 (1H, d, J=14.9), 3.75 (1H, d, J=13.3),3.68 (1H, d, J=14.9), 3.17 (1H, dd, J=12.4, 4.1), 2.91 (1H, dd, J=12.4,6.4), 2.29 (3H, s); ¹³C-NMR (DMSO-d₆) δ 145.8, 137.9, 137.4, 136.9,134.3, 131.5, 129.5, 128.7, 128.5, 128.2, 127.9, 127.3, 125.3, 121.8,114.7, 59.9, 57.5, 55.7, 46.7, 20.7; e/z (ES) 368/370 (M+1, 100%);calculated for C₁₉H₁₈N₃ C₇H₈SO₃, C, 57.78; H, 4.85; N, 7.77. found C,57.79; H, 4.85; N, 7.73.

EXAMPLE 924-(8-Benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile

A. Methyl3-[5-(t-butyl-dimethylsilanyloxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate

To a solution of the title E compound in Example 1,4-(5-t-butyl-dimethylsilanyloxy-methyl-imidazoyi-1-ylmethyl)-benzonitrile(3.15 g, 9.63 mmol) in THF (30 mL) at −78° C. is added dropwise 1.0 MLHMDS (10.0 mL, 10.0 mmol) and stirred for 10 min. Methyl bromoacetate(0.91 mL, 9.63 mmol) is added and the solution stirred for 10 min, thenquenched with ammonium chloride. On warming the reaction is partitionedbetween EtOAc and brine, thereafter the combined organic phases aredried over anhydrous sodium sulfate and removal of the solvents in vacuoyields a viscous oil. The residue is subjected to flash chromatography(silica gel) eluting with EtOAc:MeOH:NH₄OH (95:5:0.5) to give methyl3-[5-(t-butyl-dimethylsilanyloxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate:¹H-NMR (CDCl₃) δ 7.64 (2H, d, J=8.4), 7.59 (1H, s), 7.28 (2H, d, J=8.4),6.95 (1H, s), 6.05 (1H, m), 4.62 (1H, d, J=13.2), 4.46 (1H, d, J=13.2),3.66 (3H, s), 3.32 (1H, dd, J=16.3, 9.4), 3.19 (1H, dd, J=16.3, 7.0),0.83 (9H, s), 0.02 (3H, s), 0.00 (3H, s); ¹³C-NMR (CDCl₃) δ 170.0,144.8, 136.4, 133.1, 131.4, 128.9, 118.5, 112.7, 55.4, 52.7, 40.6, 26.1,18.8, −5.0, −5.1; e/z (ES) 400 (M+1, 100%).

B. Methyl3-[5-(hydroxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl]propionate

The title A compound, methyl3-[5-(t-butyl-dimethylsilanyloxymethyl)-imidazole-1-yl]-3-(4-cyanophenyl)-propionate(0.98 g, 2.46 mmol) and p-toluenesulfonic acid (0.55 g, 2.9 mmol) arestirred in MeOH (10 mL) at RT for 24 h. The reaction mixture isevaporated to an oil and partitioned between EtOAc and aqueous saturatedsodium bicarbonate. The combined organic phases are dried over anhydroussodium sulfate and removal of the solvent in vacuo yields methyl3-[5-(hydroxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate as anoil: ¹H-NMR (CDCl₃) δ 7.65 (2H, d, J=8.4), 7.62 (1H, s), 7.31 (2H, d,J=8.4), 6.98 (1H, s), 6.05 (1H, dd, J=9.2, 6.2), 4.62 (1H, d, J=13.5),4.47 (1H, d, J=13.5), 3.67 (3H, s), 3.36 (1H, dd, J=16.5, 9.2), 3.21(1H, dd, J=16.5, 6.2); e/z (ES) 286 (M+1, 100%).

C. Methyl 3-[5-formyl-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate

To a solution of the title B compound, methyl3-[5-(hydroxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate (0.60g, 2.11 mmol) in DCM (7.0 mL) is added Dess-Martin periodinane (15% wtsolution, 7.0 mL, 3.2 mmol) and the reaction is stirred for 3 h. Thereaction mixture is partitioned between EtOAc and sodiumbicarbonate-sodium thiosulfate. The combined organic phases are washedwith brine and dried (anhydrous sodium sulfate) and concentrated. Theresidue is subjected to flash chromatography (silica) eluting withEtOAc:MeOH (9:1) to give methyl3-[5-formyl-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate as an oil:¹H-NMR (CDCl₃) δ 9.68 (1H, s), 8.00 (1H, s), 7.87 (1H, s), 7.65 (2H, d,J=8.5), 7.37 (2H, d, J=8.5), 6.63 (1H, m), 3.66 (3H, s), 3.43 (1H, dd,J=16.5, 8.5), 3.30 (1H, dd, J=16.5, 6.6); ¹³C-NMR (CDCl₃) δ 178.9,169.2, 144.9, 143.0, 141.8, 132.7, 130.8, 127.4, 118.0, 112.5, 56.5,52.4, 39.0; e/z (ES) 284 (M+1, 100%).

D.4-(8-Benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile

To a solution of the title C compound, methyl3-[5-formyl-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate (0.22 g, 0.78mmol) in DCE (5 mL) is added benzylamine (0.100 mL, 0.92 mmol) followedby sodium triacetoxyborohydride (0.49 g, 2.3 mmol). The reaction mixtureis stirred at RT for 16 h, then partitioned between EtOAc and saturatedaqueous sodium bicarbonate, and the organic solution is washed withbrine, dried (anhydrous sodium sulfate) and concentrated. The residue issubjected to flash chromatography (silica) eluting with EtOAc:MeOH:NH₄OH(90:10:1) to give4-(8-benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile:m.p. 65° C.; e/z (ES) 343 (M+1, 100%).

EXAMPLE 934-(8-Cyclopropylmethyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile

The title compound is prepared analogously to Example 92: m.p. 178-180°C.; e/z (ES) 307 (M+1, 100%).

1-27. (canceled)
 28. A compound of formula I

wherein X is oxygen or H₂; Y is —CRR′— in which R and R′ areindependently hydrogen, optionally substituted alkyl, aralkyl orheteroaralkyl; R_(1a) is hydrogen, optionally substituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl orheteroaralkyl provided that R_(1a) is not 9H-carbazol-2-yl or9H-fluoren-2-yl when R₂ is methyl, m is zero or an integer of 1, n iszero, X is H₂ and R_(1b), R₃, R₄ and R₅ are hydrogen; R_(1b) ishydrogen, optionally substituted alkyl, aralkyl, heteroaralkyl, aryl orheteroaryl provided that: R_(1b) is not hydrogen when R_(1a) and R₅ arehydrogen, R₂ is methyl, X is H₂, m is an integer of 1, n is zero and Yis —CRR′ in which R and R′ are hydrogen; or R_(1b) is not hydrogen whenR_(1a) and R₅ are hydrogen, R₂ is benzyl or 3,3-dimethylallyl, X is H₂,m is zero, n is an integer of 1 and Y is —CRR′ in which R and R′ arehydrogen; or R_(1a) and R_(1b) combined are alkylene which takentogether with the carbon atom to which they are attached form a 3- to6-membered ring; R₂ is R₆—(CHR₇)_(p)— in which R₆ is optionallysubstituted alkyl, cycloalkyl, aryl or heterocyclyl; R₇ is hydrogen,optionally substituted alkyl, aryl, heteroaryl or aralkyl; p is zero oran integer from 1 to 4; R₃ and R₄ are independently hydrogen, halogen,optionally substituted alkyl, aryl or heteroaryl; or R₄—C may bereplaced by nitrogen; R₅ is hydrogen, optionally substituted alkyl,aryl, heteroaryl, aralkyl or heteroaralkyl; m and n are independentlyzero or an integer of 1 provided that the sum of m and n is not 2; or apharmaceutically acceptable salt thereof; or a diastereomer thereof; ora mixture of diastereomers thereof; or an optical isomer thereof; or amixture of optical isomers thereof.
 29. A compound according to claim 28wherein Y is —CRR′— in which R and R′ are hydrogen; or apharmaceutically acceptable salt thereof; or a diastereomer thereof; ora mixture of diastereomers thereof; or an optical isomer thereof; or amixture of optical isomers thereof.
 30. A compound according to claim 29wherein m and n are zero; or a pharmaceutically acceptable salt thereof;or a diastereomer thereof; or a mixture of diastereomers thereof; or anoptical isomer thereof; or a mixture of optical isomers thereof.
 31. Acompound according to claim 30 of formula IA

wherein X is oxygen or H₂; R_(1a) is lower alkyl, aryl or heteroarylprovided that R_(1a) is not 9H-carbazol-2-yl or 9H-fluoren-2-yl when R₆is methyl, p is zero, X is H₂, and R_(1b), R₃, R₄ and R₅ are hydrogen;R_(1b) is hydrogen, lower alkyl, aralkyl or heteroaralkyl; R₆ iscycloalkyl, aryl or heteroaryl; R₇ is hydrogen or lower alkyl; p is zeroor an integer of 1 or 2; R₃, R₄ and R₅ are hydrogen; or apharmaceutically acceptable salt thereof; or a diastereomer thereof; ora mixture of diastereomers thereof; or an optical isomer thereof; or amixture of optical isomers thereof.
 32. A compound according to claim 31wherein R_(1a) is monocyclic aryl; R_(1b) is hydrogen, lower alkyl oraralkyl; or a pharmaceutically acceptable salt thereof; or adiastereomer thereof; or a mixture of diastereomers thereof; or anoptical isomer thereof; or a mixture of optical isomers thereof.
 33. Acompound according to claim 32 of formula IB

wherein X is oxygen or H₂; R_(1b) is hydrogen, lower alkyl or aralkyl;R₆ is cycloalkyl, aryl or heteroaryl; R₇ is hydrogen or lower alkyl; pis zero or an integer of 1 or 2; R₈, R₉ and R₁₀ are independentlyhydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, optionallysubstituted alkyl, cycloalkyl, optionally substituted amino, alkoxy,alkylthio, carboxy, sulfonyl, carbamoyl, aryl, aryloxy, arylthio orheterocyclyl; or a pharmaceutically acceptable salt thereof; or adiastereomer thereof; or a mixture of diastereomers thereof; or anoptical isomer thereof; or a mixture of optical isomers thereof.
 34. Acompound according to claim 33 of wherein X is oxygen or H₂; R_(1b) ishydrogen, lower alkyl or aralkyl; R₆ is cycloalkyl, aryl or heteroaryl;R₇ is hydrogen or lower alkyl; p is an integer of 1; R₈ is hydrogen; R₉is hydrogen, halogen, cyano or trifluoromethyl; R₁₀ is halogen, cyano ortrifluoromethyl; or a pharmaceutically acceptable salt thereof; or adiastereomer thereof; or a mixture of diastereomers thereof; or anoptical isomer thereof; or a mixture of optical isomers thereof.
 35. Acompound according to claim 34 wherein X is oxygen; or apharmaceutically acceptable salt thereof; or a diastereomer thereof; ora mixture of diastereomers thereof; or an optical isomer thereof; or amixture of optical isomers thereof.
 36. A compound according to claim 34wherein R₆ is C₃₋₆cycloalkyl, monocyclic aryl or monocyclic heteroaryl;or a pharmaceutically acceptable salt thereof; or a diastereomerthereof; or a mixture of diastereomers thereof; or an optical isomerthereof; or a mixture of optical isomers thereof.
 37. A compoundaccording to claim 34 wherein R₁₀ is located at the 3-position; or apharmaceutically acceptable salt thereof; or a diastereomer thereof; ora mixture of diastereomers thereof; or an optical isomer thereof; or amixture of optical isomers thereof.
 38. A compound according to claim 28which is selected from:4-(7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Allyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(6-Oxo-7-propyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Isopropyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-{7-[2-(4-Fluoro-phenyl)-ethyl]-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl}-benzonitrile;4-[7-(3-Morpholin-4-yl-propyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;7-(4-Methoxy-benzyl)-5-(4-thiophen-3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;4-[7-(4-Methyl-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-[7-(4-Chloro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;4-[6-Oxo-7-(4-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-[6-Oxo-7-(3-methyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-[6-Oxo-7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-[6-Oxo-7-(3-trifluoromethyl-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-[6-Oxo-7-(3,4-dichloro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Cyclopropyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Cyclohexyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(7-Cyclopentyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-[7-(2-Methoxyethyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;4-[7-(3-Methoxypropyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;4-(6-Oxo-7-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;7-Benzyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-Methyl-5-phenyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-cyclopropylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-Benzyl-5-(4-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-chloro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-methoxy-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-fluoro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-cyclohexyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-methoxy-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-cyclopropylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-Benzyl-5-(3-bromo-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-chloro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(3-trifluoromethyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(3-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(3-methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-methoxy-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-chloro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(3-chloro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-methyl-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-(4-fluoro-phenethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-thiophen-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-furan-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-thiophen-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-furan-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-pyridin-3-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-pyridin-2-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-pyridin-4-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-cyclohexylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;4-[5-(3-Bromo-phenyl)-6-oxo-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-ylmethyl]-piperidine-1-carboxylicacid t-butyl ester;5-(3-Bromo-phenyl)-7-piperidin-4-ylmethyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(R)-5-(3-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(S)-5-(3-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(R)-5-(3-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(S)-5-(3-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(R)-5-(4-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(S)-5-(4-Bromo-phenyl)-7-((R)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(R)-5-(4-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;(S)-5-(4-Bromo-phenyl)-7-((S)-1-phenyl-ethyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;4-[(R)-6-Oxo-7-((S)-1-phenyl-ethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;4-[(S)-6-Oxo-7-((S)-1-phenyl-ethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;7-Benzyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-(4-Methyl-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-(4-Fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;3-(7-Benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;3-[7-(4-Methyl-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;3-[7-(4-Fluoro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;3-[7-(4-Chloro-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;3-[7-(4-Methoxy-benzyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;3-[7-(4-Fluoro-phenethyl)-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;3-(7-Phenethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;3-(7-Cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;5-(4′-Chloro-biphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-(4-Methoxy-benzyl)-5-(4-thiophen3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-Cyclopropylmethyl-5-(4-thiophen-3-yl-phenyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-Benzyl-5-(4′-fluoro-biphenyl-3-yl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-Biphenyl-4-yl-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;7-Benzyl-5-biphenyl-3-yl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one; Methyl4-(7-benzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzoate;4-(7-Benzyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;5-(4-Bromo-phenyl)-7-cyclopropylmethyl-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(3-Bromo-phenyl)-7-cyclopropylmethyl-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;5-(4-Bromo-phenyl)-7-(4-fluoro-benzyl)-5-methyl-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;4-[7-(4-Fluoro-benzyl)-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl]-benzonitrile;4-{(R)-7-[(S)-1-(4-Fluoro-phenyl)-ethyl]-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl}-benzonitrile;4-{(S)-7-[(S)-1-(4-Fluoro-phenyl)-ethyl]-5-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl}-benzonitrile;5-Benzyl-5-(4-bromo-phenyl)-7-(4-fluoro-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one;4-(5,7-Dibenzyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;4-(5-Benzyl-7-cyclopropylmethyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-5-yl)-benzonitrile;5-(4-Bromophenyl)-7-(4-methoxy-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]-pyrazine;4-(8-Benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile;and4-(8-Cyclopropylmethyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile;or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers thereof.
 39. A method for theinhibition of aldosterone synthase activity in mammals which methodcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of claim
 28. 40. A method for theprevention and/or treatment of conditions associated with aldosteronesynthase activity in mammals which method comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof claim
 28. 41. The method according to claim 40, which methodcomprises administering said compound in combination with atherapeutically effective amount of anti-obesity agent,anti-hypertensive agent, inotropic agent or hypolipidemic agent.
 42. Amethod for the treatment of hypokalemia, hypertension, congestive heartfailure, atherosclerosis, coronary heart diseases and post myocardialinfarction, which method comprises administering to a mammal in needthereof a therapeutically effective amount of a compound of claim 28.43. A method for the treatment of restenosis, increased formation ofcollagen, fibrosis, and remodeling following hypertension andendothelial dysfunction, which method comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof claim
 28. 44. A method for the treatment of renal failure andnephropathy, which method comprises administering to a mammal in needthereof a therapeutically effective amount of a compound of claim 28.45. A method for the treatment of syndrome X and obesity, which methodcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of claim
 28. 46. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 28 in combination with one or more pharmaceutically acceptablecarriers.
 47. A pharmaceutical composition according to claim 46 for thetreatment of hypokalemia, hypertension, congestive heart failure,atherosclerosis, coronary heart diseases, post myocardial infarction,restenosis, increased formation of collagen, fibrosis, remodelingfollowing hypertension and endothelial dysfunction, renal failure,nephropathy, syndrome X and obesity.
 48. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 28in combination with a therapeutically effective amount of anti-obesityagent, anti-hypertensive agent, inotropic agent or hypolipidemic agent.49. A pharmaceutical composition according to claim 48 for the treatmentof hypokalemia, hypertension, congestive heart failure, atherosclerosis,coronary heart diseases, post myocardial infarction, restenosis,increased formation of collagen, fibrosis, remodeling followinghypertension and endothelial dysfunction, renal failure, nephropathy,syndrome X and obesity.